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Prevalence of exercise-induced arterial hyposemia in female asthmatic athletes Lynn, Brenna Meaghan 2003

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P R E V A L E N C E OF E X E R C I S E - I N D U C E D A R T E R I A L H Y P O X E M I A I N FEMALE ASTHMATIC ATHLETES  by BRENNA M E A G H A N L Y N N B.H.K. The University of British Columbia, 2001  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF T H E REQUIREMENTS FOR T H E D E G R E E OF  M A S T E R OF SCIENCE in T H E F A C U L T Y OF G R A D U A T E STUDIES (School of Human Kinetics)  We accept this thesis as confirming to the required standard  T H E UNIVERSITY OF BRITISH C O L U M B I A April 2003 © Brenna Meaghan Lynn, 2003  Library Authorization  In presenting this thesis in partial fulfillment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission.  BrennaLynn  1/30/2004  Name of Author (please print)  Date (dd/mm/yyyy)  Title of Thesis:  Degree:  The Prevalence of Exercise-Induced Arterial Hypoxemia in Female Asthmatic Athletes  MSc  Department of  . Year: Human Kinetics - Faculty of Graduate Studies  The University of British Columbia Vancouver, B C Canada  2003  Abstract It has been suggested that habitual exercise training may cause mechanically or chemically mediated endothelial dysfunction during heavy exercise, which may lead to exercise-induced arterial hypoxemia. Cellular adhesion molecules E - and P-selectin have been used as direct markers of endothelial injury. Elevated plasma levels of these inflammatory mediators along with IL-6 have been present in acute lung injury and also after intense exercise. To determine whether asthmatic female athletes have higher incidence of exercise-induced arterial hypoxemia (EIAH) and higher plasma levels of soluble P-selectin and IL-6 when compared to controls, 16 female asthmatics (age = 26.4 ± 5.7 yrs; ht = 165.7 ± 7.6 cm; wt = 61.7 ± 10.9 kg; V 0 a x = 46.8 ± 8.0 mL-kg'-min" , 1  2m  range 29.3 to 57.3 mL-kg^-min" ) and 16 female non-asthmatic athletes (age = 26.2 ± 4.2 1  yrs; ht = 167.2 ± 6.8 cm; wt = 57.5 ± 6.0 kg; V 0 a x = 51.9 ± 8.2 mL-kg'^min" , range 1  2m  40.0 to 67.9 mL-kg^-min" ) were tested during the mid-follicular phase of their menstrual 1  cycle. Subjects completed an incremental maximal treadmill test on the first day of testing. Exercise-induced arterial hypoxemia (%Sa02 < 93%) was seen in 7 of the 16 asthmatics and 8 of the 16 control subjects. On day 2 during the run to exhaustion test, 6 of 16 asthmatics decreased %Sa02to less than 93%, whereas 9 of the 16 controls developed EIAH. The data failed to show significance (p >0.05) in %Sa0 between 2  groups on Day 1 (p = 0.74) and Day 2 (p = 0.93). There was a significant decrease in saturation over time for both groups (p = 0.00 and p = 0.00). P-selectin and IL-6 were . measured on Day 2 by enzyme immunoassay before and after the treadmill run to exhaution test. With exercise, there was a significant change over time for both Pselectin (p = 0.00) and IL-6 (p = 0.00). No significant group by time interaction was seen  ii  in pre-post concentration of P-selectin (p = 0.37) or IL-6 (p = 0.43). There was however a significant difference in pre-post concentration of IL-6 (p = 0.04) between those controls that displayed EIAH and those that did not develop EIAH. No significance was seen in asthmatics with respect to IL-6 and EIAH. Plasma concentrations of soluble Pselectin (p = 0.94) and IL-6 (p = 0.27) were not significantly different between groups. No statistical significance was apparent in P-selectin and hypoxemia between groups. The incidence of EIAH in an asthmatic population is not significantly higher in asthmatics when compared to controls. The increased levels in plasma P-selectin and IL6 after intense exercise may represent endothelial dysfunction. However, increased plasma level of P-selectin and IL-6 were seen in both groups and therefore cannot support the hypothesis that asthmatics show increased levels of inflammatory markers due to lung damage from chronic-recurrent high stresses of breathing during exercise training.  iii  Table of Contents Abstract  ii  List of Tables  v  List of Figures  vi  List of Abbreviations  viii  Acknowledgements  xi  Introduction  1  Methods  5  Participants  5  Research design  5  Diagnosis of asthma  6  Day One  7  Eucapnic Voluntary Hyperpnoea Test  7  Maximal aerobic capacity  8  EIAH  9  Day Two  9  Enzyme linked immunoassay - soluble selectins  9  Human IL-6 immunoassay  10  Statistical analysis  10  Results  11  Discussion  31  References  40  Appendix A. Literature Review: Asthma and exercise  52  Appendix B. Literature Review: Exercise immunology  70  Appendix C. Literature Review: Exercise-induced arterial hypoxemia  82  Appendix D. Table-Individual Data  100  Appendix E. Figures  112  iv  List of Tables  Table 1. Aerobic activity of control (CS) and asthma subjects (SA)  12  Table 2. Physical characteristics for control and asthma subjects  13  Table 3. Baseline spirometry values at rest for control and asthma subjects  13  Table 4. Physiological parameters at maximal exercise for control and asthma subjects  14  Table 5. Pre and post concentrations of P-selectin and IL-6 for control and asthma subjects  20  Table 6. Saturation values and changes in P-selectin and IL-6 between groups  20  Table 7. Age, height, mass and E V H scores of individual subjects  100  Table 8. Individual subjects hormonal parameters for both testing days  101  Table 9. Resting lung volumes of individual subjects on Day 1  102  Table 10. Resting lung volumes of individual subjects on Day 2  103  Table 11. Ventilatory parameters at peak exercise of individual subjects on Day 1  104  Table 12. Ventilatory parameters at peak exercise of individual subjects on Day 2  105  Table 13. Performance at peak exercise of individual subjects on Day 1  106  Table 14. Performance at peak exercise of individual subjects on Day 2  107  Table 15. Individual %Sa02 data measured during progressive exercise on  108  Day 1 Table 16. Individual %Sa02 data measured during progressive exercise on Day 2  109  Table 17. Individual pre- and post-exercise concentration of sP-selectin  110  Table 18. Individual pre- and post-exercise concentration of IL-6  111  v  List of Figures  Figure 1. Minimum %Sa02 data for asthmatics and controls versus V 0 during the V0 xtest  21  Figure 2. Minimum %Sa02 data for asthmatics and controls versus V 0 during the R T E  21  Figure 3. Mean % S a 0 for control subjects during the V 0  22  2  2ma  2  2  2max  test  Figure 4. Mean %Sa02 for asthma subjects during the VO2 max test  22  Figure 5. Mean %Sa02 for control subjects during the R T E  23  Figure 6. Mean % SaO*2 for asthma subjects during the R T E  23  Figure 7. Individual mean pre- and post-exercise plasma concentrations of sP-selectin for controls  24  Figure 8. Individual mean pre- and post-exercise plasma concentrations of sP-selectin for asthmatics  24  Figure 9. Individual mean pre- and post-exercise plasma concentrations of IL-6 for controls  25  Figure 10. Individual mean pre- and post-exercise plasma concentrations of IL-6 for asthmatics  25  Figure 11. Relationship between AsP-selectin concentration and minimal % S a 0 for controls  26  2  Figure 12. Relationship between AsP-selectin concentration and minimal %Sa02 for asthmatics  26  Figure 13. Relationship between AIL-6 concentration and minimal %Sa02 for controls  27  Figure 14. Relationship between AIL-6 concentration and minimal %Sa02 for controls  27  Figure 15. Relationship between AsP-selectin concentration and airway function (EVEf) for controls  28  vi  Figure 16. Relationship between AsP-selectin concentration and airway function (EVH) for asthmatics  28  Figure 17. Relationship between AIL-6 concentration and airway function (EVH) for controls  29  Figure 18. Relationship between AIL-6 concentration and airway function (EVH) for asthmatics  29  Figure 19. Relationship between airway function (EVH) and minimal %Sa02 for controls  30  Figure 20. Relationship between airway function (EVH) and minimal %Sa02 for asthmatics  30  Figure 21. EIA standard curves for A. soluble P-selectin, B. IL-6  112  vii  List of Abbreviations  A-aD0 a ANOVA 2  P  CAM EVH ECT EIA EIAH FEVi FEF FVC HR IOC MCT P0  m a x  2  PA0  2  Pa0 PaC0 PC 2  2  2 0  PFT RM ANOVA RER %Sa0 sE-selectin sP-selectin V V /Q V0 2  E  A  2  vco vo  2  2max  VWF:Ag  (ideal) alveolar/arterial P 0 gradient alpha analysis of variance beta cell adhesion molecule eucapnic voluntary hyperpnoea test exercise challenge test exerice-induced asthma exercise-induced arterial hypoxemia forced expiratory volume in 1 second maximal forced expiratory flow forced vital capacity heart rate International Olympic Committee methacholine challenge test partial pressure of oxygen alveolar partial pressure of oxygen arterial partial pressure of oxygen arterial partial pressure of carbon dioxide concentration of agent that will provoke a 20% fall in F E V i pulmonary function test repeated measures analysis of variance respiratory exchange ratio percent arterial oxyhemoglobin saturation soluble E-selectin soluble P-selectin minute ventilation ventilation perfusion ration rate of oxygen consumption rate of carbon dioxide production maximal oxygen consumption von Willebrand factor antigen 2  VM  Acknowledgements  I am so thankful for so many positive things that have happened to me over the last few years of my life, I would like to thank the people who have been involved. First, I would like to thank Dr. Don McKenzie for being a wonderful supervisor and friend. Don, your wisdom and insight are second to none, thank-you for taking the time to get to know me as a person and. for inspiring me and everyone else around you to be better.  A special thank-you to Diana Jespersen, for help on so many matters; from laboratory frustrations to advice on life. Another of my fellow students describes Diana as our "UBC mom" and I would have to agree.  I would also like to thank my committee members, Dr. Bill Sheel and Dr. Bob Levy for their time and assistance on important issues. I cannot forget to mention Dr. Keith Walley and the lab technicians, in particular Shelley Dai, at St. Paul's hospital for their generous help with the analysis for my study.  The subjects in my study need a special mention for selflessly giving up their time. Most of the women in the study were close friends, so they could not say no even if they wanted to.  Thanks to all my fellow students at Allan McGavin, my endless questions did not seem to phase them. Thanks to Alastair Hodges and Mike Koehle, their help was key to the completion of my thesis. I cannot thank Ian Stewart enough for his friendship and academic support over the last few years. Kiwi you are the best, someday I will attempt to repay you for all your help.  Finally I would like to thank my family. I could not have asked for more supportive wonderful people to have as parents. Dad I will one day take you to Yankee Stadium. Thanks to my sister Erin, who means to world to me.  ix  Introduction Asthma is a chronic inflammatory disease of the airways characterized by an increased response of the trachea and bronchi to a variety of stimuli (American Thoracic Society, 1987). Airway diameter can be affected by chemicals, microbiological viruses, physical exercise, and immunologic allergens; these stimuli influence the pattern and severity of the disease (Lemanske et al., 1997). Asthma is characterized by eosinophil degranulation, and plasma cell infiltration (Cutz et al., 1972). These inflammatory cells release mediators that are responsible for the clinical manifestation of the disease. The asthmatic patient will experience episodes of breathlessness, wheezing, chest tightness, coughing and increased mucous production. Asthmatic athletes will have variable symptoms and these may be limited to dyspnea, inappropriate to the exercise task, post exercise cough and a decrease in performance (McKenzie, 1991). Endothelial dysfunction is central to acute lung injury. Endothelial cellular adhesion molecules (CAMs), E - and P- selectin are involved with neutrophil-endothelial and platelet-neutrophil interactions. E - and P- selectin have been increased in endothelial activation and injury and have been detected in patients at risk for acute lung disease (Kayal et al., 1998). E - and P- selectin have also been increased with various types of strenuous exercise. Grissom et al. (1997) found elevated plasma levels of soluble E selectin in 17 subjects with acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE); there was a correlation between E-selectin and the degree of hypoxemia. Conversely P-selectin was not altered with the ascent to altitude, AMS or HAPE. Eldridge et al. (1998) reported significantly increased levels of E-selectin at 3810 meters. Hunte (2000, unpublished data) found no change in plasma E-selectin in fourteen  2  habitually active eumenorrheic female endurance athletes after an incremental cycle test; conversely there was a significant rise in concentration of plasma P-selectin. Pulmonary gas exchange efficiency was maintained at peak exercise in ten subjects, decrements in arterial saturation were seen in three subjects, while the remaining subject showed mild hypoxemia (%Sa0 94%). 2  IL-6 is a cytokine and is produced locally in the skeletal muscle, is known to have growth factor abilities and is said to be a key immune mediator in an inflammatory response. IL-6 is also expressed by a variety of normal and transformed cells. Cytokines facilitate an influx of lymphocytes, neutrophils, and monocytes, which help in the clearance of antigens and ultimately aid in healing (Pedersen, 2000).  IL-6 is the type of  cytokine that is produced in the largest amount in response to exercise. Researchers found IL-6 to be increased by 100-fold after a marathon run (Northoff et al., 1991). Fifty-six runners were tested from the Copenhagen Marathon in 1996-1998 and research the runners with the fastest running times were found to have the highest IL-6 levels (DeRijk et al., 1994). IL-6 levels have been shown to increase significantly 30 min after the start of running and peak after 2.5 hours of running (Ostrowski et al., 1998). Rivier et al., (1994) examined the effects of strenuous exercise on the release of cytokines. Ten male, endurance trained young athletes and 6, endurance trained master athletes performed an incremental cycle test to exhaustion. Blood samples were taken before and after exercise and 20 minutes following the maximal cycle test. There was no correlation between the release of IL-6, T N F - a and lung function measured during hypoxemia. They concluded that these inflammatory mediators do not play a role in the development of hypoxemia.  3  Dempsey and Wagner (1999) define mild exercise-induced arterial hypoxemia (EIAH) as an arterial saturation (%Sa0 ) of 93 - 95% (or 3-4% <rest), moderate E I A H 2  as 88 - 93%, and severe EIAH as less than 88%. With the above definition in mind, decreases in arterial P 0 and oxyhemoglobin saturation (%Sa0 ) have been demonstrated 2  2  during intense exercise in elite male athletes ( V 0  2 p  eak  >  65 mL-kg" -min" ) (Dempsey et 1  1  al., 1984; Powers et al., 1988; McKenzie et al., 1999; Rice et al., 1999), male masters athletes (Prefaut et al., 1994), and female aerobic athletes (Harms et al., 1998; St.Croix et al., 1998; Wetter et al., 2001). Dempsey et al. (1984) showed that there was gas exchange impairment in fit male athletes at submaximal work levels. Harms et al. (1998) demonstrated that female athletes displayed exercise-induced arterial hypoxemia (EIAH), and greater reductions in Pa0 and %Sa0 at the same submaximal intensity when 2  2  compared to control subjects. The mechanisms responsible for the development of EIAH have been discussed and debated over the last fifteen years. Ventilation/perfusion inequality (V /Q), diffusion A  limitation, veno-arterial shunt and relative hypoventilation have been suggested to play a role in EIAH, whether individually or collectively (Dempsey et al, 1999). The incidence rate of E I A H in asthmatics has not yet been determined and this is the purpose of this research paper. EIAH is not well understood in most populations, as limited research exists for female subjects and for individuals with varying levels of fitness and respiratory disease. Exercise may cause endothelial dysfunction in the lung as inflammatory mediators have been found in human plasma after exercise. Asthma is characterized by inflammation; asthmatics show injury to the alveolar epithelium. Asthmatics may be susceptible to severe and more prevalent EIAH due to diffusion  limitation from edema and inflammation. The link between capillary endothelial dysfunction due to exercise and alveolar epithelial injury associated with asthma and E I A H is not clear and needs to be investigated. .With these theories in mind the research hypotheses state that: 1. The incidence of exercise-induced arterial hypoxemia will be greater in an active female asthmatic population compared to the female control subjects 2. The severity of EIAH will be greater in asthmatics when compared to an elite athletic population. 3. Plasma levels of soluble P-selectin and IL-6 will increase with maximal exercise in the asthma and control group however, the increase will be greater in the asthmatic subjects and the magnitude of this increase will be related to those subjects with greater impairment of pulmonary gas exchange.  5  Methods Participants Sixteen female asthmatics and 16 female control subjects were recruited by posted notices at the University of British Columbia and by third party referral. All subjects were nonsmokers and between the ages of 18 and 40 years in order to keep the prevalence of other diseases to a minimum. Subjects had no history of pulmonary, cardiac, vascular or autoimmune diseases. Only the asthmatic patients had a history of asthma. Only eight of the asthmatic subjects were receiving regular pharmacological treatment for their asthma. Six subjects took therapeutic doses of short acting beta-2 agonists and 4 subjects were using inhaled corticosteriods. Leucotriene inhibitors were not used in the group of asthmatics. Subjects had variable fitness levels with a minimum level of 3 to 5 hours per week of total exercise time. Informed consent was obtained in writing and subjects were free to withdraw at any time from the study. Study procedures were approved by the Clinical Research Ethics Board of the University of British Columbia. Research design Subjects were required to report to the Exercise Physiology Lab at the Allan McGavin Sports Medicine Centre on two separate occasions. Asthmatic subjects were permitted to use their asthma medications for the incremental V 0 2  m a x  test and the running  to exhaustion test (RTE) and were tested during the mid-follicular stage of their menstrual cycle (Day 5 to 9). Exercise tests were separated by a minimum of 24-hours.  6  Diagnosis of asthma The diagnosis of asthma can be confirmed by a methocholine challenge test (MCT), an exercise challenge test or eucapnic voluntary hyperpnoea test (EVH). In the present study, E V H was used to confirm the diagnosis of exercise-induced asthma (EIA) (Anderson et al., 2001). In this test the athlete must hyperventilate dry air that contains 5% carbon dioxide at room temperature for a total of 6 minutes at a target ventilation of 30 times the athlete's forced expiratory volume in one second (FEVi). A reduction of F E V i of 10% or more from the baseline value indicates a positive diagnosis of asthma. Baseline F E V i was measured three times before the challenge and the highest value was used to calculate the airway response. F E V i was measured immediately after the E V H test at 0 minutes and then again in recovery at 3, 5, 10, 15 and 20 minutes. The response is classified as mild when the fall in F E V i is between 10 and 19.9% and when the ventilation is 60% maximum voluntary ventilation ( M W ) . A moderate response is defined as a fall between 20 and 29.9% in F E V i . The response is severe when the fall in F E V i is 30% or more at any level of ventilation.or if a fall greater than 10% occurs at a ventilation rate less than 30%) M W . In North America the methacholine challenge test is the gold standard tests for the diagnosis of asthma (Malo et al., 1983). Aerosols (containing methacholine) are administered using a Wright nebulizer attached to a facemask, calibrated to deliver the aerosols at a rate of 0.13 mL-min" . Aerosols are then inhaled for periods of 2 minutes 1  followed by 30 and 90 second F E V i determinations. After a baseline F E V i is established with saline, methacholine is inhaled in doubling concentrations (0.125, 0.25,0.5, 1.0, 2.0, 4.0, 8.0 and 16.0 mg-min" ) every 5 minutes (Juniper et al., 1991). F E V i is measured 1  every 30 and 90 seconds after each concentration until a fall in F E V i of 20% (PC20) is achieved when compared to the saline control. If a concentration of 16 mg •mL" is 1  tolerated without a 20% change in F E V i , this indicates a negative test. Subjects were required to have a minimum 10% decrease of F E V i on the E V H test (Anderson et al., 2001) or a PC20 less than or equal to 8 mg-min" on M C T (Malo et al., 1983) in order to 1  be considered an asthmatic subject for this study. Day One Following measurement of height and mass, pulmonary function was measured using spirometry (Medical Graphics Metabolic cart with 1070 Pulmonary Function Software). Forced expiratory volume in 1 second (FEVi), forced vital capacity (FVC) and maximal forced expiratory flow ( F E F  max  ) were measured and compared to predicted  normal values. All control subjects and asthmatic subjects without diagnostic confirmation of asthma, then completed a eucapnic voluntary hyperpnoea test (EVH). Those asthmatic subjects with results of a methacholine challenge test (MCT) or an exercise challenge test (ECT) provided a copy of the results to the investigators on this day. Eucapnic Voluntary Hyperpnoea Test (EVH) The E V H test requires that no short-acting bronchodilators, sodium cromoglycate, nedocromil sodium or ipratropium bromide be taken for 8 hours prior to testing, and no long-acting bronchodilators or sustained release bronchodilators or antihistamines be used for 48 hours prior to testing. No leukotriene antagonists were allowed for 4 days prior to the test. Inhaled steroids were not permitted on the day of the E V H test. Subjects were asked to refrain from caffeine on the morning of the study. Subjects were  8  asked not participate in vigorous exercise 24 hours prior to testing and from food, 4 hours prior to testing. In this test subjects hyperventilated dry air containing 5% carbon dioxide at room temperature for a total of 6 minutes, at a target ventilation 30 times the forced expiratory volume per second (FEVi). Baseline F E V i values were then compared to F E V i values 0, 3, 5, 10, 15 and 20 minutes following the E V H test. Maximal aerobic capacity All subjects completed a VO2 max test to determine baseline aerobic capacity. After an individual warm-up each participant underwent an incremental maximal exercise test on a treadmill ergometer. The treadmill velocity started at 2.22 m/sec and increased by 0.22 m/sec per minute until 3.54 m/sec was reached and then an increase of 2% in grade every minute occurred until the subjects experienced volitional fatigue. Subjects were tested with the K4b portable metabolic unit (COSMED K4b Rome, Italy). Heart 2  2  rate was measured continuously with a portable heart rate monitor (Polar Vantage X L , Kempele, Finland). Following an application of a topical vasodilator nitrate cream (Finalgon, Boehringer Ingelhein, Burlington, ON) an ear oximeter (Ohmeda Biox 3740, Louisville, CO) was then attached to the left pinna for measurement of %Sa02. Ventilatory, gas exchange, heart rate and %Sa0 parameters were averaged and recorded 2  every 15 seconds using a computerized data system (K4b ). 2  V02max was measured and  confirmed by attainment of 3 of the following 4 criteria, volitional fatigue, peak heart rate within 10% of predicted max, respiratory exchange ratio (RER) greater than 1.10, and/or a plateau in V 0 an with increased workload. At the end of the session a questionnaire 2  pertaining to dyspnea was given to determine the severity of the symptoms following the exercise tests.  9  EIAH Exercise-induced arterial hypoxemia (EIAH) was determined with an ear oximeter (Edwards et al., 1999). During exercise, subjects who had a percentage of oxygen saturation (%SaC>2) of 93 % (less than 5% of initial resting values) were classified as having mild EIAH, subjects that had %Sa02 of 88 - 92% were classified as having moderate EIAH and those subjects with values less than 88% were classified as having severe E I A H (Dempsey and Wagner, 1999). Day Two All subjects performed a constant workload treadmill run test to exhaustion test. After a brief individual warm-up, subjects ran for 3 minutes at a treadmill velocity corresponding to 50% of VC^maxand at then 3 more minutes at 75% of V02max (established on Day 2). Then the treadmill velocity was increased to 90 % of their V O 2 max and the subjects ran until volitional fatigue was reached. A physician drew 10 mL  /  blood samples (cubital vein) at the beginning and one hour after the end of exercise. Similar protocols to Day 1 were used to determine pulmonary function, heart rate, maximal oxygen uptake and blood oxygenation levels. At the end of the exercise session a questionnaire pertaining to dyspnea was given to determine the severity of the symptoms that followed the exercise tests. Enzyme linked immunoassays - soluble selectins Plasma concentrations of soluble P-selectin were measured by enzymelinked immunoassays (EIA) (Bender MedSystems, Vienna;BMS219/2) as per manufacturer's instructions. Minimal limits of detection for each assay are <1.3 ng- mL  - 1  for sP-selectin. Standards and samples were run in duplicate. Optical density was read at  10 450nm with correction at 620nm. A standard curve was plotted and selectin concentration was determined by interpolation from a straight-line equation. The manufacturer reported the coefficient of variation for P-selectin to be 4% and below. Human IL-6 immunoassay Concentration of Interleukin IL-6 was measured by enzyme-linked immunoassay (EIA) (R&D Systems, Minneapolis; HS600B) as per manufacturer's instructions. Minimal limits of detection for the assay range from 0.016-0.110 pg-mL" . The 1  standard and samples were run in duplicate. Optical density was read at 450nm with correction at 620nm. A standard curve was plotted and IL-6 concentrations were then determined by interpolation from a straight-line equation. The manufacturer reported the coefficient of variation for IL-6 to be 9.6% and below. Statistical analysis Means and standard deviations were calculated for all variables. Differences between pre- and post-exercise concentrations of IL-6 and sP- selectin were analyzed by a 2x2 A N O V A with repeated measures (RMANOVA) (SPSS™). A 2x4 R M A N O V A was performed to show changes in P-selectin and IL-6 values with those asthmatics and controls that maintained arterial saturation and those that dropped to 93% and below (EIAH). Arterial saturation was the dependent variable for both groups (2) x VO2 values at baseline, 25%, 50%, 75%, 90% and 100% were the independent variables (6) with repeat measures. Spirometry values before and after the E V H test was assessed by way of a 2x7 R M A N O V A . 2x6 R M A N O V A was used to assess changes in spirometry before and after the V02maxtest and the R T E test. Scheffe's post-hoc test was used to show difference in groups when significance was found. Significance was set at a <0.05.  11 Results Descriptive characteristics All subjects were involved in regular aerobic activity in the 12 months preceding this study. Self- reported data indicated that the asthmatic subjects were involved in aerobic activity between 3 and 6 days per week (average = 5.5 ± 2.6 hrs/week), controls subjects reported 4 to 6 days per week (average = 6.8 ± 3.3 hrs/week). Control subjects were more involved in intense aerobic activity compared to the asthmatic subjects (Table 1). No statistical significance was seen in physical characteristics, baseline spirometry or physiological parameters between the asthmatics and controls. Anthropometric data is presented in table 2. All subjects were tested between day 5 and 9 of their menstrual cycle. Twelve of the 16 control subjects and 9 out of the 16 asthmatic subjects were taking oral contraceptives. Only one of the control subjects was amenorrheic as compared with two asthmatic subjects, the remainder of the subjects were eumenorrheic. Confirmation of diagnosis Two subjects had a diagnosis of asthma confirmed with a methacholine challenge test; the average value for the two subjects was less than 4 mg-mL" . All other subjects 1  underwent a eucapnic voluntary hyperpnoea test (EVH) to either confirm a positive or negative diagnosis of asthma. E V H results for the asthma group showed a mean F E V i % decrease of 17.8 + 10.3 % vs 6.4 ± 2.1 % for the control group. These results classified the asthma group as having mild asthma. Specifically, the E V H test classified two  12  subjects as severe and 12 subjects as having mild asthma. Baseline spirometry values from both testing days are shown in Table 3.  Table 1. Aerobic activity of control (CS) and asthma subjects (SA) Number of Days/week  Subject  Average Volume in hours per week (hrs/week)  CS1  4-6  6  CS2 CS3  5 5-6  5 8  CS4  4  4  CS5 CS6  5-6 4-5  4.5 7  CS7  4-7  15  CS8 CS10  6 5-6  6 7.5  C S 11  6  9  CS12 CS13 CS14  6 10 3.3  CS15 CS17  6 5 5 5 6-7  CS18  2  2  Mean ± SD  4.89 + 1.29  6.82 ± 3 . 2 8  SA1  6  8  SA2  4  6  SA3  6  9  SA4  4-5  6  SA5  6  9  SA6  4  3  SA7  3-4  3  SA8  3  4  SA9  5-6  5  SA10  4  4  SA11 SA12  3-4 4  4 4  SA13  5  3.75  SA15  5  5  5 10  SA16  5-6  5  SA17  6-7  12  .  Mean ± SD  4.56 ± 1.01  5.52 + 2.57  13  Table 2. Physical characteristics for control and asthma subjects  Age, yrs Height, cm Mass, kg Cycle on Day 1, days Cycle on Day 2, days  Control (n= 16) 26.19 + 4.18 167.22 ± 6 . 8 1 57.52 ± 6 . 0 3 6.38 ± 1.80 7.69 ± 1.80  Asthmatic (n = 16) 26.38 ± 5 . 7 1 165.68 ± 7 . 5 9 61.73 ± 10.94 6.15 + 1.82 8.38 ± 1.80  Values are mean ± SD; yrs, years; cm, centimetres; kg, kilograms; days, time period of the menstrual cycle; there are no statistically significant differences between groups.  Table 3. Baseline spirometry values at rest for control and asthma subjects Day 1 F E V I , litres F V C , litres FEV1/FVC, percent 25-75%, percent FEFmax, L-sec" 1  Day 2 F E V I , litres F V C , litres FEV1/FVC, percent 25-75%), percent FEFmax, L-sec" 1  Control (n= 16)  Asthmatic (n = 16)  3.35 ± 0 . 4 6 (104 ± 1 1 . 9 ) 3.90 ± 0 . 5 3 (103 ± 10.4) 86.42 ± 6 . 1 7 (101 ± 7 . 8 ) 3.82 ± 0 . 8 1 (99 ± 2 0 . 8 ) 6.62 ± 1.29 (106 ± 19.5)  3.20 ± 0 . 6 2 (93 ± 2 9 . 7 ) 3.89 ± 0 . 6 1 (105 ± 1 1 . 0 ) 81.60 ± 9 . 4 1 (95 ± 10.4) 3.64 ± 0 . 9 6 (89 ± 2 8 . 6 ) 5.94 ± 1.89 (98 ± 2 0 . 2 )  3.30 ± 0 . 4 3 (102 ± 10.9) 3.77 ± 0 . 5 5 (100+ 11.4) 84.92 ± 1 1 . 1 5 (100 ± 13.1) 3.96 ± 1 . 1 2 (100 ± 2 0 . 4 ) 6.85 ± 1.23 (111.2 ± 16.1)  3.14 ± 0 . 5 6 (98 ± 14.6) 3.70 ± 0 . 6 0 (100 ± 12.4) 84.70 + 5.91 (99 ± 6 . 6 ) 3.45 ± 0 . 9 3 (92 ± 2 4 . 7 ) 6.69 ± 1.09 (107 ± 17.6)  Values are mean ± SD; F E V i , forced expiratory volume in one second; F V C , forced vital capacity; F E V i / F V C , ratio of F E V i to F V C ; 25-75%, percent of forced expiratory volume occurring between 25 and 75% of the curve; FEFmax, maximal forced expiratory flow in litres per second; bracketed numbers are percent predicted values±SD; there are no statistically significant differences between groups.  14  Table 4. Physiological parameters at maximal exercise for control and asthma subjects Day 1 HR, bpm V E , litres-min" VO2, litres-min" V0 x, mL-kg'^min" V C 0 , litres-min" RER RTE, minutes Day 2 HR, bpm V E , litres-min" VO2, litres-min" 1  1  1  2ma  1  2  1  1  V0 ax, mL-kg^-min" VCO2, litres-min" RER R T E , minutes  1  2m  1  Control (n= 16)  Asthmatic (n = 16)  191.1 ± 7 . 3 103.1 ± 8 . 9 3.0 ± 0 . 6 51.9 ± 8 . 2 3.5 ± 0 . 6  188.5 ± 10.2 100.5 ± 2 1 . 0 2.8 ± 0 . 4 46.8 ± 8 . 0 3.3 ± 0 . 4  .1.18 ± 0.1  1.18 + 0.0  N/A  N/A  189.6 ± 8 . 7 102.1 ± 1 2 . 8 2.9 ± 0 . 4 51.3 ± 4 . 9 3.3 ± 0 . 6 1.15 ± 0 . 1 6.51 ± 1.8  187.7 ± 11.5 96.8 ± 16.9 2.8 ± 0 . 5 47.2 ± 8 . 4 3.2 ± 0 . 4 1.13 ± 0 . 1 5.18 ± 2 . 3  Values are mean ± SD; HR, heart rate in beats per minute; V E , minute ventilation in litres per minute; VO2, maximal rate of oxygen consumption in litres per minute; V02max, maximal rate of oxygen consumption in millilitres per kilogram per minute; VC0 2 , rate of carbon dioxide production in litres per minute; RER, respiratory exchange ratio; R T E , time in minutes to exhaustion at 90% of max treadmill velocity determined on Day 1; there are no statistically significant differences between groups.  Exercise parameters Maximal exercise values from the V02maxtest on Day 1 are shown in Table 4. Control subjects demonstrated aerobic values from 2.2 to 4.3 L-min  (40.0 to 67.9  mL-kg^-min" ; mean =2.98 ± 0.59 L-min ) . Asthmatic subjects had aerobic capacity 1  values ranging from2.3 to 3.4 L-min  -1  _ 1  (29.3 to 57.3 mL-kg^-min" ; mean = 2.78 ± 0.36 1  L-min ). This represents a wide range of activity levels in both groups, from moderate _1  to highly trained females. Maximal exercise values for the Run to Exhaustion (RTE) test on Day 2 are shown in Table 4. The control subjects demonstrated aerobic values from  15  2.3 to 3.8 L-min  _ 1  (42.5 to 58.9 rriL-kg'^min" ;mean = 2.94 ± 0.43 L-min 1  subjects had aerobic capacity values ranging from2.1 to 3.9 L-min mL-kg^-min" ; mean = 2.85 ± 0.50 L-min 1  _ 1  Asthmatic  (29.1 to 65.65  Control subjects had higher levels of  aerobic fitness but this was not statistically significantly different from the asthmatic group. Maximal exercise was indicated by volitional fatigue. The respiratory ratio (RER) during the VO2 max test on Day 1 exceeded 1.10 in all but 1 asthmatic and 1 control subject. On Day 2 during the run to exhaustion test 3 asthmatics and 2 control subjects did not reach RER values higher than 1.10. Peak heart rate within 10% of predicted (226-age) was achieved in all but 3 asthmatics and 2 controls on Day 1. On Day 2 peak heart rate was again achieved in all female subjects with 4 asthmatics and 3 controls being slightly below the predicted values.  Spirometry data A 2x7 R M A N O V A was performed on spirometry values after the E V H test at the time points: baseline, 0, 3, 5, 10, 15 and 20 minutes. Statistical analysis on F E V i data showed there was a significant difference between the asthmatic and control subjects (p = 0.021). There was a change over time for both groups (p = 0.001), and there was a significant difference with time by group difference (p = 0.021). The changes in F E V i values occurred between: baseline and 0 minutes, baseline and 3 minutes, baseline and 5 minutes, baseline 15 minutes and baseline and 20 minutes with the E V H test (p =0.000 for all time points). Statistical analysis on F V C data showed a significant change over time for both groups. However, there was no significant difference between groups (p = 0.628) or with time by group interaction (p = 0.427).  A 2x6 R M A N O V A was used to analyze spirometry data after the both exercise tests at the time points: baseline, 0, 3, 5, 10, and 15 minutes. Statistical analysis from spirometry data after the V02max and R T E test failed to show a significant difference between groups. F E V i data after VC>2max test showed no significant difference between the asthmatic and control subjects (p = 0.103). There was a change over time (p = 0.000), but there was no significance with time by group difference (p = 0.295). There was a significant difference in F E V i (p = 0.000) at baseline to 0 minutes during the VO"2 xtest. ma  Statistical analysis on F V C data after V02max test showed no significant changes over time (p = 0.088), with groups (p = 0.603), or with time by group interaction (p = 0.631). The R T E test showed no significant changes in spirometry values with groups. F E V i data revealed that there was a significant change over time for both groups (p = 0.000). There were no significant differences between groups (p = 0.069) and time by group interaction (p = 0.098). Statistical analysis on F V C data showed no significant differences with time (p = 0.088), time by group (p = 0.538) nor was there any difference seen between asthma and control groups (p = 0.722). Pulmonary gas exchange Ventilatory parameters V E , V C O 2 , V O 2 and RER were measured for controls and asthmatics on both testing days; a significant difference was not seen between groups, nor was statistical significance seen in these parameters for each group from Day 1 to Day 2. There was also no statistical significance seen between run time to exhaustion (controls = 6.5 ± 1 . 8 minutes; asthmatics = 5.2 ± 2.3 minutes). V O 2 and heart rate (FIR) were also measured at maximal exercise on both days, no statistical significance was seen in either group.  17 Dyspnea Subjects were asked to rate the level of dyspnea they felt upon fatigue at the end of the exercise bout on a scale of 1 to 10 (1 = no symptoms; 10 = severe dyspnea). On Day 1 only one control subject attributed termination of exercise to dyspnea, whereas eleven asthmatics reported symptoms related to dyspnea at maximal exercise. These symptoms following maximal exercise were described by asthmatics as chest tightness, wheezing, constriction and difficulty exhaling. On Day 2, five control subjects reported dyspnea associated with exercise. Fourteen of the 16 asthmatics reported asthma-like symptoms at maximal exercise. Asthma subjects described symptoms of chest tightness, wheezing, constriction, and demonstrated a post-exercise cough.  EIAH Dempsey and Wagner (1999) defined mild to moderate EIAH as Sa0 values < 94 2  - 95% or a 3-4%> decrease from baseline. %Sa0 was determined by an ear oximeter, and 2  as oximeter values are approximately 1%> lower than arterial blood values (Edwards et al. 1999), EIAH was defined as %>Sa0 <93%. 2  Saturation was maintained in 9 asthmatic and  8 control subjects during the V02maxtest on Day 1. Seven of the 16 (43.8%) asthmatics showed decreases in Sa0 % of 93% or greater, whereas 8 of the 16 (50%) controls 2  subjects demonstrated decreases to 93%> or lower in Sa0%>. On Day 2 saturation was 2  maintained in 10 asthmatic and 7 control subjects. Six of the 16 (37.5%) asthmatics showed decreases in Sa0%> of 93%> or greater, whereas 9 of the 16 (56.3%) controls 2  subjects demonstrated decreases of 93% or more in Sa0 %. Minimal %Sa0 of 90%) was 2  2  seen in one asthmatic subject and 2 control subjects displayed minimal saturations of 88%o. No significant differences in %Sa0 were seen between groups on Day 1 and Day 2  18  2 (p = 0.735 and p = 0.930 respectively). However, both Day 1 and Day 2 showed significance difference in time (p = 0.000 and p = 0.000). Differences for the VChmaxtest were seen between each time point with the exception of rest and SaCh at 25% (p = 0.06). This means that saturation was significantly decreasing at all time points except there was no significant change in %Sa02 from rest to 25% VO2 max for each group. Time by group interaction was significant for the R T E test on Day 2 (p = 0.03) and not significant for the VO2 max test (p = .317). All time points for the R T E were significant with the exception of %Sa02 between baseline and 25% and 75 and 90%. This data shows that there were significant changes in %Sa0 from rest to 25% and also at 75 to 90% of VCbmax2  Soluble P-selectins A 2x2 RMANOVA failed to show any significant difference in plasma concentrations of soluble P-selectin in either group or time by group interaction (p = .939, p = .369 respectively) (pre-exercise asthmatic = 194.8 ± 199.3 ng-mL" ; post-exercise 1  asthmatic = 249.7 ± 246.8 ng-mL" ; pre-exercise control = 173.4 ± 128.0 ng-mL ; post1  -1  exercise control = 279.8 ± 201.2 ng-mL" ). Statistical analysis showed a significant 1  effect of change over time (p = 0.008) in P-selectin values. A 2x4 RMANOVA revealed no significant group and time by group difference in pre-post exercise concentrations of sP-selectin (p = .540, p = .627) between those control and those asthmatic subjects who displayed normal gas exchange and subjects who displayed mild to moderate exerciseinduced hypoxemia. Significance was observed with change in time (p = .009) in Pselectin values.  19 Human Interleukin- 6 (IL-6) A 2x2 R M A N O V A showed significance change in time in Interleukin-6 (IL-6) concentrations before and at the end of exercise (p = 0.002). No significant difference was seen with group or time by group interaction (p = .274, p = .431) in IL-6 concentrations (pre-exercise asthmatic = 0.47 ± 0.46 pg-mL ; post-exercise asthmatic = -1  0.91 ± 0.94 pg-rnL" ; pre-exercise control = 0.6113 ± 0.70 pg-mL ; post-exercise control 1  -1  = 1.30+1.15 pg-rnL ). A 2x4 R M A N O V A showed a significant group and time -1  difference was seen in pre-post exercise concentration of IL-6 (p = 0.035, p = 0.010) between controls and asthmatics that displayed normal gas exchange compared to subjects that developed mild to moderate EIAH. Scheffe's post-hoc test revealed that there was a significant difference in IL-6 values from pre to post exercise for only control subjects that showed exercise-induced arterial hypoxemia. Table 5 shows pre and post-exercise P-selectin and IL-6 concentrations. Table 6 shows oxyhemoglobin saturation data of both groups with respect to P-selectin and IL-6 values before and after exercise. Figures 7-10 show the relationship between pre- and post-exercise concentrations of inflammatory markers. Figures 11-14 display the relationship between absolute change in sP-selectin and IL-6 concentrations and minimal %Sa02. Figures 15-18 shows the relationship between inflammatory markers and airway function. Figures 19-20 displays the relationship between airway function and minimal %Sa0 . 2  20  Table 5. Pre and post concentrations of P-selectin and IL-6 for control and asthma subjects Control (n=14) P-selectin (ng-mL ) IL-6 (pg-mL )  Pre-Exercise  Post-Exercise  173.43 ± 128.01 0.61 ± 0 . 7 0 *  279.75 ± 2 0 1 . 2 0 *  Asthmatic (n =12)  Pre-Exercise  Post-Exercise  194.79 + 199.28 0.47 + 0.46  249.74 + 246.78* 0.91 ± 0 . 9 4 *  -1  -1  T  P-selectin (ng-mL ) IL-6 (pg-mL ) -1  1.30 + 1.15*  A Values 124.32 0.69  % change  A Values 54.95 0.44  % change 28.21 93.62  71.68 113.11  Values are mean + SD; P-selectin, plasma concentration of soluble P-selectin in nanograms per millilitre; IL-6, plasma concentration of Interleukin-6 in picograms per milliliter; A Values, change in plasma concentration of inflammatory marker P-selectin and IL-6 with exercise; % change, change in plasma concentration of inflammatory markers expressed as a percent; * significance, p<0.05 Table 6. Saturation values and changes in P-selectin and IL-6 between groups Controls (n = 13) Variable  Day 2 EIAH (n = 8)  MinSa0 (%)  Mean + SD 91.11 ± 2 . 0 9  No E I A H (n = 5) Mean ± SD 95.14 ± 1.68  AP-selectin Values (ng-mL )  90.76 ± 108.12  134.33 ± 183.04  AIL-6 Values (pg-mL )  0.96 ± 1.33*  0.27 ± 0 . 2 1  Asthmatic (n =12) Variable  Day 2 EIAH (n = 6)  No EIAH (n = 6)  2  -1  -1  93.17 + 1.17  Mean ± SD 95.5 ± 0 . 9 7  AP-selectin Values (ng-mL )  89.75 ± 8 9 . 7 5  20.15 ± 0 . 5 6  AIL-6 Values (pg-mL )  0.40 ± 0 . 4 9  0.47 ± 0 . 4 7  Mean + SD MinSa0 (%). 2  -1  -1  Values are mean + SD; EIAH, exercise-induced arterial hypoxemia; min Sa0 , minimal arterial oxyhemoglobin saturation in percent; AP-selectin, absolute change in plasma concentration of soluble P-selectin in nanograms per millilitre; AIL-6, absolute change in plasma concentration of Interleukin-6 in picograms per milliliter; * significance, p<0.05 2  Figure 1. Minimum %Sa02 data for asthmatics (SA) and controls (CS) versus VO2 during the VChmax test  100 98 96 -I 94 92 90 88 86 0  mm *  o % S a 0 2 (SA) • % S a 0 2 (CS)  1 Oxygen Consumption (L/min)  Figure 2. Minimum %Sa02 data for asthmatics (SA) and controls (CS) versus VO2 during the R T E  100 98 96 94 92 90 H 88 86  « %Sa02 (AS) ia %Sa02 (CS)  1 Oxygen Consumption (L/min)  Figure 3. Mean %SaC>2 for control subjects during the VO2 max test  0  25  50  75  90  100  Percentage of O x y g e n C o n s u m p t i o n (%)  Figure 4. Mean %Sa02 for asthma subjects during the  S  .2 w  | <  100,  88 86 -J  , 0  1  25  1  50  1  75  1  90  100  Percentage of Oxygen Consumption (%)  VC^maxtest  Figure 5. Mean % SaC>2 for control subjects during the R T E  0  25  50  75  90  100  Percentage of O x y g e n Consumption (%)  Figure 6. Mean % SaC>2 for asthma subjects during the R T E  1c  100-,  0  25  50  75  90  100  Percentage of Oxygen Consumption (%)  24 Figure 7. Individual mean pre- and post-exercise plasma concentrations of sP-selectin for controls  1000  n  Pre  Post  Figure 8. Individual mean pre- and post-exercise plasma concentration of sP-selectin for asthmatics  Pre  Post  25 Figure 9. Individual mean pre- and post-exercise plasma concentrations IL-6 for controls  5  n  Pre  Post  Figure 10. Individual mean pre- and post-exercise plasma concentrations of IL-6 for asthmatics  3 E  5 -, 4-  Pre  Post  26  Figure 11. Relationship between AsP-selectin concentration and minimal %Sa02 for controls  100 98 96 +- ^ • E „> ™ a» 94 £ c « >,2 « 92 90 O 2 Sc 88 — 3 LU .2 % "E ™ 86 aj co  <  R = 0.0335 2  100  200  •  300  400  C h a n g e sP-selectin (ng/mL)  Figure 12. Relationship between absolute AsP-selectin concentration and minimal %Sa02 for asthmatics  c  !5  100 98 o -*—» 3 96 E o (1) 94 c (A cu c £ 92 X 0 o O to fe 90 XJ TOco U 88 86 B w 0 O)  X  R = 0.0012  CO  2  s  100  200  300  Change sP-selectin (ng/mL)  400  Figure 13. Relationship between AIL-6 concentration and minimal %Sa02 for controls  c !n o D) o E a) x: >.  x O  15  o  100 ^  98  R  = 0.002  *  96 94 92 90 88 86 0.2  0.4  0.6  0.8  Change in IL-6 (pg/mL)  Figure 14. Relationship between AIL-6 concentrations and minimal %SaC>2 for asthmatics  100 98 96 94 92 0) x 90 LU 88 86  R = 3E-05 2  •  •  •  •  0.2  0.4  0.6  Change in IL-6 (pg/mL)  0.8  28 Figure 15. Relationship between AsP-selectin concentration and airway function (EVH) for controls  45 40 35 30 25 20 15  >  LU O o  R = 0.0308 2  10*  CO  X  ~9  >  LU -200  H  -100  f  0  100  200  300  C h a n g e in P-selectin (ng/mL)  Figure 16. Relationship between AsP-selectin concentration and airway function (EVH) for asthmatics  C h a n g e in P-selectin (ng/mL)  29  Figure 17. Relationship between AIL-6 concentration and airway function (EVH) for controls  >  LU O U CO I >  LU  45 40 35 30 25 20 15 10 -I 5 4  R = 0.0023 2  —&  1 C h a n g e in IL-6 (pg/mL)  Figure 18. Relationship between AIL-6 concentration and airway function (EVH) for asthmatics  LU  ?2 _  0.064  O U  CO  X  >  LU C h a n g e in IL-6 (pg/mL)  Figure 19. Relationship between airway function ( E V H ) and minimal % S a 0 for controls 2  V  > LL B L< U k_  o O CO X  > LU  45 i 40 35 30 25 20 15 10 50 86  R = 0.0001 2  • I - S - T 88  90  92  94  96  98  100  Minimal Saturation (%Sa0 ) 2  Figure 20. Relationship between airway function ( E V H ) and minimal %Sa02 for asthmatics  -y 45 ^ 40 35 30 25 20 15 10 5 0  H  tf = 0.0352  H  86  88  90  92  94  96  Minimal Saturation (%Sa0 ) 2  98  100  31  Discussion The findings from this study demonstrate a similar prevalence of E I A H in females with asthma in comparison to a control group. In the exercise tests there were no significant differences in any physiological parameter measured at the end of the maximal aerobic capacity assessment or the RTE. In addition, measurement of soluble Pselectin and IL-6 were not different between groups before or after the RTE. Following the exercise tasks, F E V i was decreased to the same degree in both groups. With the lack of significant differences between the asthmatic and control groups, the diagnosis and severity of asthma requires further consideration. The E V H test was chosen to confirm the diagnosis of asthma. This test appears to be the optimal laboratory challenge to confirm that an athlete has exercise-induced asthma; it has been performed on thousands of subjects in both the laboratory and in the field. The E V H can simulate the respiratory demands of exercise in terms of high minute ventilation and changes in temperature and air conditions. It is known as a reliable test to provoke bronchoconstriction and it has a very high specificity for identifying persons with clinically recognized asthma (Anderson et al., 2001). Many recent studies have commented on the sensitivity and specificity of the E V H test. These studies show that the E V H test is better than an exercise challenge test in diagnosing asthma (Eliasson et al., 1992; Mannix et al., 1999). The E V H test is a widely used and highly recommended test for diagnosing asthma. The subjects in this study showed a mean decrease in F E V i of 17.8% for asthmatics and 6.4% for the control subjects. This is statistically significantly different and characterizes the asthmatics as mild. This is supported by the low use of anti-  32 asthmatic medication. Only 8 of 16 females with a diagnosis of this disease were regularly using medication. Only 4 subjects were taking inhaled corticosteroids. On the basis of this clinical information and the results of the E V H , these subjects can be classified as very mild asthmatics. Although the post  V02max and R T E spirometry was not different between groups,  there are valid explanations for this observation. As performance was the primary outcome measure, the asthmatic subjects were allowed to use their medications prior to the exercise task. This would have a significant influence in the pre and post exercise spirometry. In addition each subject was instructed to do a warm-up prior to initiating the exercise test, both the V02max and R T E test begin with a modest workload and progress to more intense exercise. The intensity at the end of the task was 100% of maximal effort. The response to an exercise challenge in an asthmatic population is influenced by a number of factors. Warm-up, the progression of exercise, the exercise mode and exercise intensity all affect the asthmatic response. In the standard exercise challenge test, the subject must run at 80% of V 0  2ma  x for 6 to 8 minutes with no warm-up, this is  significantly different when compared to the protocol used in this study. The methodology used in this study allows an extended warm-up, the subjects exercised for a longer time and the intensity is much higher than during an exercise challenge test. For all of these reasons the post-exercise F E V i changes in these mild asthmatics were not significantly different from the control group. The individual components of the thesis will now be discussed.  33  EIAH In this descriptive study of thirty-two female athletes, (sixteen asthmatics and sixteen controls subjects) with varying levels of aerobic fitness, the results demonstrate that 7 of 16 asthmatics and 8 of 16 control subjects had mild to moderate exerciseinduced hypoxemia (EIAH) during the V02m test and 6 of 16 asthmatics and 9 of 16 ax  controls had mild to moderate EIAH (SaC>2 <93%) during the run to exhaustion test. These results are consistent with a recent study by Wetter et al. (2001) authors found the prevalence of exercise-induced arterial hypoxemia (EIAH) to be approximately 47% in habitually fit female athletes with V 0 2 m a x ranging from 44 to 56 mL-kg^-min" . EIAH 1  was much more severe in a previously reported study of 29 female runners (V02max ranging from 35 to 70 mL-kg^-min" ), where 22 of the 29 subjects demonstrated gas 1  exchange impairment (Harms et al., 1998). The prevalence of EIAH reported by Hopkins et al. (2000) and Hunte et al., (unpublished data) was much lower and not consistent with these findings. Hopkins et al. (2000) found the prevalence of EIAH to be approximately 24%) (4 of 17 subjects); however, it is important to note that this study did not control for menstrual cycle. Hunte et al. (unpublished data) did control for menstrual cycle and found EIAH in 4 of 14 habitually active female subjects. It is interesting to note that in this study, cycling was chosen as the mode of exercise. Studies that have found prevalence rate of EIAH to be 50% and above, have used running as the mode of exercise (Harms et al. 1998; St. Croix et al., 1998; Wetter et al., 2002). It is currently believed that treadmill running causes greater decreases in EIAH when compared with cycling due to the higher ventilatory demand. This was shown in a study by Gavin and Stager (1998); researchers found lower %SaC<2 with an ear oximeter during running when  34  compared to cycling. Recent studies have confirmed EIAH to be approximately 50% in highly trained male endurance athletes (VChmax^ 68 mL-kg" -min" ) (Dempsey et al., 1  1  1984; Powers et al.1988; McKenzie et al, 1999; Rice et al., 1999). It is also known that EIAH has adverse effects on performance and VChmax (Koskolou and McKenzie, 1994; Powers et al., 1988). It seems evident that male and female endurance athletes develop EIAH, but the prevalence seems to be higher in females at much lower fitness levels. Airway function The two groups of subjects in this study showed similar baseline spirometry values and statistical analysis demonstrated there were no differences in spirometry between groups after the exercise protocols. Asthmatic and control subjects displayed a normal pattern of response to exercise, this was shown by changes in pulmonary function. Spirometry values had significant changes over time indicating that measures of pulmonary function were affected by bronchodilation possibly due to decreased vagal tone from the release of catecholamines (Spector, 1993). It seemed that spirometry values were highest in asthmatics and controls directly after exercise, most likely due to the catecholamine response. Then values slowly decreased until a return to normal range was seen between 15 and 20 minutes. This is consistent with the typical physiological pattern of EIA and ventilation after exercise (Anderson, 1988). Interestingly enough in this study, most asthmatics attributed dyspnea as the limiting factor for volitional fatigue at maximal exercise, whereas controls attributed volitional fatigue more to "heavy legs" or muscular tiredness than to limitation in ventilation. Other symptoms reported by the subjects were wheezing, chest tightness, constriction and shallow breathing. These symptoms were experienced by both groups, although they were more prevalent in the  35  asthmatic athletes, as 12 out the 16 asthmatics reported symptoms of dyspnea. The pulmonary data shows no difference in the physiological response to exercise between groups, thus the described symptoms appear to be subjective differences. Severity of asthma In the present study asthmatics with an E V H score of a 10% decrease or more in F E V i from baseline were included. Anderson et al. (2001), define bronchial responsiveness from the E V H test as mild, moderate and severe. The response is mild if the fall in F E V i is between 10 and 19.9%, when the ventilation is 60% M W or more, and moderate when the decreases are between 20 and 29.9%. A severe response is classified as a fall in F E V i greater than 30%> at any ventilation. The mean decrease in F E V i was 16%> for the asthmatic group. The results contend that EIAH is not related to the severity of asthma. In a study by Ienna and McKenzie (1994), there was no significant difference in V E , VO2, RER, %Sa02 and lactate in those subjects with severe versus mild asthma. They concluded that severity of asthma did not appear to have a great disturbance on physiological parameters during exercise. The results of this study are consistent with these findings as EIAH was not more prevalent in asthmatic females compared to controls.  EIAH  and asthma Exercise-induced arterial hypoxemia has not yet been examined in a male  asthmatic population. This is the first study that has investigated EIAH in female asthmatics. It is thought that the asthmatic experiencing gas exchange impairment, and other problems due to asthma may be more physiologically stressed at maximal exercise. The purpose of this study was to investigate whether or not asthmatics have a higher  36 prevalence of E I A H when compared to the highly and moderately trained athlete. Deal and colleagues (1979) believe that changes in ventilation have direct impact on ;  respiratory heat loss, which in turn has effects on the amount of post-exercise bronchoconstriction. This might impact performance in highly trained asthmatic athletes, due to high minute ventilation and perhaps result in a higher prevalence of EIAH. Wetter et al., (2001) examined 17 fit women to determine the effects of pulmonary gas exchange and airway function during a run to exhaustion test. These researchers assessed airway reactivity by way of a methacholine challenge test (MCT). Two of the 16 subjects were classified as asthmatics by a positive M C T (PC2o 4 <  mg-mL" ) and three additional subjects were considered to have borderline bronchial 1  hyperresponsiveness (PC20 =4-16 mg-mL" ). The rest had normal bronchial 1  responsivenss. They concluded that airway reactivity did not correlate with exerciseinduced changes in total respiratory resistance or exercise-induced arterial hypoxemia. These results of Wetter et al. (2001) are consistent with the findings of the thesis. It is interesting to note that in the present study the asthmatic that had the lowest %SaO"2 (90%) on each day of testing had only a mild 10% reduction in F E V i at the end of the Eucapnic Voluntary Hypernoea test (EVH). The asthmatic with the greatest drop in F E V i (43%o) (PC o= 5.25 mg-mL" ) had no major decrease in %Sa02from baseline 1  2  (%Sa0 =96%). 2  E I A H and exercise parameters The discrepancy in the prevalence of EIAH seen in the asthmatic subjects compared to the control subjects may be due to the higher level of fitness in the control subjects. For example control subjects demonstrated aerobic values from 2.2 to 4.3  37  Lmirf (40.0 to 67.9 mL-kg" -min" ). Asthmatic subjects had aerobic capacity values 1  1  1  ranging from2.3 to 3.4 L-min" (29.3 to 57.3 mL-kg" -min" ). Controls had longer run 1  1  1  times to exhaustion when compared to asthma subjects (controls = 6.5 ± 1.8 minutes; asthmatics = 5.2 + 2.3 minutes), these times are not statistically different. This study examined the effect of constant speed, high-intensity exercise to exhaustion on performance parameters and EIAH.  This protocol was similar to that used in a study by  Wetter et al., (2001), as this exercise bout is more typical of race-like situation than a progressive exercise test. During progressive maximal exercise EIAH was seen in 4 of 16 asthmatics with a V 0 2 m a x  >  50 mL-kg" -min" and 3 of 16 asthmatics with a V 0 2 1  1  50 mL-kg" -min" . EIAH was seen in 5 of 16 control subjects with a V C 1  1  '•min" and 3 of 16 controls with a V O " 2 m a 1  < X  ,  2max  >  m a  x  <  mL-kg"  50 mL-kg" -min" . The findings suggest there 1  1  is no greater prevalence of EIAH in an active female asthmatic population when compared to non-asthmatic control subjects and that EIAH might be more dependent on training history. Inflammatory mediators and the prevalence of E I A H In the present study there were no significant differences in IL-6 or soluble Pselectin within groups during maximal exercise. However there were significant changes over time with IL-6 and P-selectin. Demonstration of a significant relationship between P-selectin and gas impairment was not seen, as there were no significant differences in Pselectin in those subjects who did and did not develop EIAH. A significant difference was seen in control subjects who developed EIAH and changes in IL-6, but no relationship between IL-6 and EIAH was apparent in the EIAH and non-EIAH asthmatic subjects. Are results are consistent with results from at study by Rivier et al., (1994)  38  where authors examined the effects of strenuous exercise on the release of cytokines. Ten male, endurance trained young athletes and 6, endurance trained master athletes performed an incremental cycle test to exhaustion. Blood samples were taken before and after exercise and 20 minutes following the maximal cycle test. The spontaneous release of T N F - a and IL-6 was significantly increased in the young athlete group compared to the master athlete group. When all subjects were considered together IL-6 was significantly increased at the end of exercise and slightly but not significantly decreased during the post-exercise recovery. There was no correlation between the release of IL-6 and T N F - a and lung function measured during hypoxemia. • They concluded that it could not be confirmed that these inflammatory mediators play a role in hypoxemia. Wetter et al. (2002) examined the role of lung inflammatory mediators as a cause of EIAH. They hypothesized that ventilation-perfusion mismatch and diffusion limitation might cause edema through high-pulmonary pressure and vascular leakage. The results showed that after drug administration there were no significant differences in inflammatory markers and they concluded that airway inflammation is insufficient to cause gas impairments and EIAH in young athletes. The findings demonstrate plasma levels of soluble P-selectin and EL-6 did increase over time but there were no differences seen between the asthma and control groups. The increase was higher with IL-6 concentration in control subjects with EIAH. There was no relationship between those subjects with E I A H and greater magnitudes of increase in P-selectin and IL-6. The third hypothesis stated that the increase would be higher with the asthmatic subjects due to the role of airway inflammation and asthma. Larsson et al., (1993) described a higher prevalence of asthma and airway inflammation in high-level athletes. This may indicate  39  that individuals with chronic high intensities and duration of exercise may develop asthma-like conditions. It was originally thought that asthmatic athletes would show greater changes in the concentrations of inflammatory markers due to exercise training with repeated stress. These findings can not explain EIAH in asthmatics as there were no significant differences of inflammatory cells, the asthmatics did not have higher levels of IL-6 or P-selectin after strenuous exercise when compared to the control group and therefore this data does not support the original hypothesis. Conclusion In summary, this study reports the prevalence of exercise-induced arterial hypoxemia to be 38% (6/16) in asthmatics during a maximal incremental treadmill test (Day 1) and 44% (7/16) during a constant speed high-intensity test (Day 2). Controls demonstrated an prevalence rate of 44% (7/16) on Day 1 and 50% (8/16) on Day 2. E I A H was seen in 4 of 16 asthmatics with a V02max 50 mL-kg" -min" and 3 of 16 >  1  !  asthmatics with a V02max 50 mL-kg" -min" . EIAH was seen in 5 of 16 control subjects >  1  1  with a V02max> 50 mL-kg^-min" and 3 of 16 controls with a V02max< 50 mL-kg" -min" . 1  1  1  Differences in arterial saturation between groups may be attributed to differences in fitness level. The prevalence of EIAH during treadmill running appears to be approximately 50%>. A significant rise in P-selectin and IL-6 with exercise, was seen in both groups but there were no significance differences between groups. There was a significant difference in IL-6 with control subjects that displayed EIAH. No difference was seen in asthmatics with EIAH and inflammatory markers. 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Thomson JM, Dempsey JA, Chosy LW, Shadhidi NT, Redden WG. Oxygen transport and oxyhemoglobin dissociation during prolonged muscular work. J Appl Physiol 31: 658-664, 1974. Tilz GP, Domej W, Diez-Ruiz A, Weiss G, Brezinschek R, Brezinschek HP, Hutel E , Pristautz H, Wachter H, Fuchs D. Increased immune activation during and after physical exercise. Immunobiol 188: 194-202,1993.  50  Waalkens HJ, van Essen-Zandvliet, Gerritsen J, Duiverman EJ, Kerrebijn KF, Knol K, and the cutch CNSLD study group. The effect of an inhaled corticosteroid (budesonide) on exercise-induced asthma in children. Eur Respir J 6: 652-656, 1993. Wagner PD, Erickson BK, Seaman J, Kubo K, Hiraga M , Kai M , Yamaya Y. Effects of altered FIO2 on maximum VO2 in the horse. Respir Physiol 105: 123-134, 1996. Wagner PD. Ventilation-perfusion matching during exercise. Chest 101: S192-S198, 1992. Wagner PD, Hoppler H, Saltin B. Determinants of max O2 uptake. In: The lung, edited by R G Crystal and JB West. New York: Raven, p.1585-1594, 1991. Wagner WW Jr, Latham LP, Hanson WL, Hofmeister SE, Capen RL. Vertical gradient of pulmonary capillary transit times. JAppl Physiol 61: 1270-1274, 1986. Wagner PD. Influence of mixed venous p 0 on diffusion across the pulmonary bloodgas barrier. Clin Physiol 2: 105-115, 1982. 2  Ward PA. Recruitment of inflammatory cells into lungs: roles of cytokines, adhesion molecules, and compliment. J Lab Clin Med 129: 400-404, 1997. Warren G, Cureton K,Middendorf W, Ray C, Warren J. Red blood cells pulmonary capillary transit time during exercise in athletes. Med Sci Sports Exerc 23: 1352-1361, 1991. Weight L M , Alexander D, Jacobs P. Strenuous exercise: analogous to the acute-phase response? Clin Sci 81: 677-683, 1991. West J, Wagner P. Ventilation-perfusion relationships. In Crystal et al. (Eds) the lung: scientific foundations. Pp. 1289-1306. Raven Press. New York. 1991. West J. Respiratory physiology - the essentials. Williams and Wilkins. Baltimore MD. 1995. Wetter TJ, Xiang Z, Sonetti DA, Haverkamp HC, Rice AJ, Abbasi AA, Meyer K C , Dempsey JA. Role of lung inflammatory mediators as a cause of exercise-induced arterial hypoxemia in young athletes. JAppl Physiol 93: 116-126, 2002. Wetter TJ, St. Croix C M , Pegelow DF, Sonetti DA, Dempsey JA. Effects of exhaustive endurance exercise on pulmonary gas exchange and airway function in women. J Appl Physiol 91: 847-858,2001. Williams JH, Powers SK, Stuart MK. Hemoglobin desaturation in highly trained athletes during heavy exercise. Med Sci Sports Exerc 18: 168-172,1986.  51  Voy RO. The U.S. Olympic Committee experience with exercise-induced bronchospasm, 1984. Med Sci Sports Exerc 18: 328-330, 1986.  52 Appendix A : Review of the Literature: Asthma and exercise Introduction to asthma The mortality and morbidity associated with asthma are increasing for unknown reasons in many parts of the modern world, causing global health concerns. The clinical manifestations and therapeutic responses of asthma in patients of all ages indicate that it may be more of a syndrome rather than a specific disease entity. Viral infections, exercise, and exposure to irritants and allergies complicate the short and long term management of asthma (Lemanske et al. 1997). Asthma is a chronic inflammatory disease of the airways, it is characterized by an increased response of the trachea and bronchi to a variety of stimuli (ATS, 1987). The asthmatic patient will experience episodes of breathlessness, wheezing, chest tightness, coughing and mucous production. These symptoms may interfere with sleep patterns and activities of daily living. The patient must endure administration of medications sometimes on a regular basis. The physician must devise a therapeutic plan that will maximize control over the disease and minimize negative side effects. Asthmatic athletes will have variable symptoms and the symptoms may be limited to dyspnea, inappropriate to the exercise task, post-exercise cough and sometimes decreases in performance, if symptoms are not well controlled (McKenzie, 1991). Asthma consists of airway obstruction, secondary to bronchial smooth muscle spasm and of airway inflammation, which may consist of edema, mucous secretion, and the influx of inflammatory cells. Appropriate medications must be chosen based on severity of the disease, patterns of disease activity and age of onset.  53 Asthma creates bronchial smooth muscle hypertrophy, mucous hypersecretion, and airway inflammation. The responsiveness to the airway diameter can be a result of chemicals, microbiological viruses, physical exercise, and immunologic allergens, these stimuli influence the patterns of disease. With these factors in mind, defining asthma is a difficult task. Lemanske et al. (1997) defined asthma as a disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, and T lymphocytes. In affected individuals, the inflammation causes coughing and wheezing and breathlessness particularly at night or in the early morning. These episodes are due to airflow obstruction that can be reversible with treatment. The pathophysiology and the genetics associated with asthma The genetics of asthma is a topic that has recently been reviewed (Sanford et al. 1996). Most researchers agree that asthma has a significant hereditary component. The genetics associated with asthma is complex (Lemanske et al, 1997). This disease cannot be simply classified as having a dominant, recessive, or sex-linked inheritance. The genetics of asthma are difficult to pin-point, even though the disease has very recognizable clinical features, the disease has multiple contributing factors, and variability of disease onset and severity. Links to chromosome 1 lql3 and the high-affinity IgE receptor (Cookson et al., 1989), linkage to chromosome 5q and the cytokine gene cluster, linkage to 5q and bronchial responsiveness and linkage to chromosome 14q and the T-cell antigen receptor have been suggested as possible gene candidates. Environmental factors must be considered and more completely defined for expression of the disease phenotype (Sanford et al., 1996). Variables of the pVadrenergic receptor gene were evaluated to see  54 if they could in some way be linked to asthma (Reihsaus et al., 1993). Nine different mutations were identified and one mutation substitution of glycine for arginine at position 16 was associated with more severe asthma (Reihsaus et al., 1993). Airway obstruction Contraction of bronchial smooth muscle narrows the airways and causes an increase in airway resistance. This may be due to stimulation of receptors in the lining of the airways by irritants such as cigarette smoke and dust. This is regulated by the autonomic nervous system. Bronchodilation occurs as a result of stimulation of the adrenergic receptors; drugs such as isoproterenol and epinephrine have the same bronchodilation action and are useful in the treatment of asthma. Parasympathetic activity and acetylcholine cause bronchoconstriction, the injection of histamine into the pulmonary artery causes smooth muscle contraction in the alveolar ducts (West, 1995). Airway obstruction in asthmatic patients is a result of pathogenetic abnormalities (Lemanske et al., 1997); these abnormalities vary among patients and are hypothesized to contribute to diversity of clinical symptoms and disease severity. Airway limitation must be due to bronchial smooth muscle spasm due to the immediate responsiveness of the airway with the use of bronchodilators (Bai et al, 1992). From this evidence it can be suggested that the function of bronchial smooth muscle in asthmatic patients is abnormal (Lemanske et al, 1997). Post-mortem biopsies from patients who have died from asthma have shown hypertrophy of the smooth muscle lining in the airways (Bai et al, 1990). These authors have suggested that these patients have a greater maximal response to a contractile agonist and impaired relaxation.  55 Airway inflammation Airway inflammation is thought to be the principal mechanism defining the intensity of bronchial hyperreponsiveness in asthma. The lining of the airways contains a number of inflammatory cells such as mast cells, alveolar macrophages, eosinophils, lymphyocytes, neutrophils, basophils and platelets, which are capable of generating a wide variety of mediators that can induce bronchospasm. Edema of the airway mucosa is due to increased capillary permeability with leakage of serum proteins into interstitial spaces (Lemanske et al., 1997). Histamine, prostaglandin, platelet activating factor and bradykinin are responsible for inducing edema (Frick et al., 1987). Increased bronchovascular permeability occurs due allergen exposure (Frick et al., 1987). Edema and inflammation can result in increased airway thickness and therefore airway narrowing for asthmatic patients (Lemanske et al., 1997). Inflammation in asthmatic patients Inflammation of the airways is a major feature for patients that have died of status asthmaticus (McFadden et al., 1992). Other major findings from biopsies have shown that there is evidence of mucous plugging, collagen deposition, edema of the submucosa, infiltration of leukocytes, and smooth muscle hypertrophy, these findings differ from patients who have died from COPD and cystic fibrosis, where airway neutrophilia is prevalent (Salvato, 1968). Asthma is characterized by eosinophil degranulation, and plasma cell infiltration. Cutz et al. (1972) compared lung biopsy from 2 children who were in remission from bronchial asthma and 2 children who had died from status asthmaticus. The only notable differences were a larger number of submucosal eosinophils and more extensive denudation of the epithelium in the fatal asthma patients.  56 In the last few years the understanding of resident cells present in asthma is due to the larger number of publications that reported on biopsies obtained from the lung (Lemanske et al., 1997). McFadden et al. (1992) have reported changes in patients with mild to moderate asthma: denudation of the airway epithelium, collagen deposition beneath the basement membrane, mast cell degranulation, and lymphocyte and eosinophil infiltration and activation. Other research has reported the presence of various cytokines such as tumor necrosis factor, interleukin (IL) 18, EL-5, IL-6, granulocyte-macrophage colony-stimulating factor (Broide et al., 1992). These cytokines have very complex mechanisms and have the ability to induce the expression of various cell adhesion molecules. This provides an inflammatory cell adhesion and migration from the circulation into the lamina propria and into the airway (Leff et al., 1991). There is much to be learned regarding inflammation and asthma, as it plays a major role in the therapeutic management of the disease (Lemanske et al., 1997). Because many lung diseases are characterized by airway inflammation, cell migration, cell location and activation, and expression of cell adhesion molecules need to be further understood, explored and defined. Patterns of disease activity Symptoms are variable for each asthmatic patient. Patients may experience significant decreases in pulmonary function over a period of minutes, hours or days. Alterations in pulmonary function will cause immediate need for medication or medical help. The severity of exacerbations may also vary between patients and in the same patients based on perception of the disease and the baseline level of lung function as a result of airflow limitations and airway hyperresponsiveness (Lemanske et al., 1997).  57 Factors that contribute to the onset of asthma a)  Allergens Exposure to allergens is the most common precipitating factor for both adult and  adolescent asthmatics. The allergen response involves the following key features: antigen-specific IgE antibody, tissue mast cell and circulating basophils, which binds the IgE antibody through high-affinity cell surface receptors, antigen bridging of at least 2 IgE molecules on the surface of mast cells, and the mast cell release to the various target organs (Lemanske et al., 1997). The IgE-mediated reactions are a major contributor to both chronic and acute airway inflammation (Niemeijer et al., 1992). Martinez and associates (1995) have shown that elevated levels of IgE measured between 9 and 12 months of age are a significant risk factor for the persistence of wheezing illness after 3 years of age. The long-acting pVagonist salmeterol has also been shown to be capable of blocking both the early and late responses of allergens (Pizzichini et al., 1996). b)  Viral infections Viral respiratory infections can cause episodes of asthma in some patients.  Johnston et al. (1995) and Nicholson et al. (1996) provided evidence showing that the viruses were the cause of wheezing in nearly 80% of asthma exacerbations, a virus called rhinovirus was the predominant virus detected. This was seen in patients of all ages. There is evidence that rhinovirus infections promote the development of the late allergic reaction, enhance eosinophil recruitment to the airway and cause eosinophil infiltration into the airway (Calhoun et al., 1994). There is other evidence stating that respiratory viruses can stimulate the generation of pro-inflammatory cytokines including IL-lp\ tumor necrosis factor a, and IL-11 (Einarsson et al., 1996). This suggests that these  58 viruses enhance existing allergic inflammation by promoting the production of inflammatory mediators and up-regulating existing airway inflammation. Exercise as a precipitating factor of asthma Exercise is one of the most common precipitants of airway limitation in asthmatic patients. It is now known that exercise is just another stimulus in provoking an asthmatic episode. When exercise is the provoking factor, then inflammation and airway responsiveness may not be involved (Jarjour et al., 1992). Exercise-induced asthma (EIA) affects 50 to 80% of patients with asthma as well as 40% of patients with allergic rhinitis (Kowabori et al., 1976). The symptoms of EIA may include wheezing, coughing, shortness of breath and chest pain. Bronchospasm usually occurs 1 to 15 minutes following intense exercise. However, the symptoms are most intense for 5 to 10 minutes after the end of an exercise bout. Given a sufficient exercise stimulus of 85% of maximal oxygen consumption for 4 to 10 minutes the pattern of EIA is fairly common (Mannix et al. 1999). Bronchodilation is the initial response to exercise in healthy and asthmatic subjects, the may be caused by the release of catecholamines. Catecholamines are released from the adrenal medulla by the sympathetic nerves. Bronchodilation is transient and peaks mid-exercise and returns to normal resting values at the end of exercise (Cypcar et al., 1994). Bronchospasm may occur at 5 to 10 minutes after the end of exercise and in most cases is not severe enough to be life threatening. Failure of normal catecholamine release during exercise may be responsible for this post exercise airway narrowing seen in EIA. Asthmatics have a decrease in plasma noradrenalin and this may inhibit the release of catecholamines. Pulmonary function returns to normal within 30 to 60 minutes after an exercise bout (Fitch and Godfrey, 1976).  59  The physiology of EIA During exercise, the lungs must support the increase in metabolic rate from the exercising muscles; this is accomplished by increasing ventilation, by the uptake of oxygen and increasing the excretion of carbon dioxide. To maintain adequate airflow the airways should remain maximally dilated, although matching of airflow to blood flow requires control of the diameter of the airway, which is accomplished by contraction of the airway smooth muscle (Beck, 1999). Maintaining normal airway function requires correct fluid content and ensuring adequate ciliary function (Al-Bazzaz, 1986). Bronchodilation of the airway is the initial physiological response to exercise (Anderson et al., 1975) in normal patients, however in EIA, bronchodilation will reverse within 5 to 8 minutes of near-maximal exercise. Most patients will recover within 20 to 60 minutes of the termination of exercise, however there is incidence of late-phase asthma that occurs 3 to 13 hours after exercise and spontaneously resolves (Speelberg et al., 1992). EIA is typically observed after exercise but more recent studies suggest that bronchospasm may actually occur during exercise (Tan et al., 1998). If the individual attempts to exercise after the symptoms have stopped, then fewer symptoms will be present the second time. This is known as the refractory period and it has been documented to last between 40 minutes and 3 hours (Tan et al., 1998). Chemical mediators such as histamine causes smooth muscle contraction, and it also alters capillary permeability, causing fluid exudation. Leukotrienes and prostaglandin PGD2 are released by inflammatory cells and airway epithelial cells and cause bronchoconstriction, PGE2 causes bronchodiliation and it is released by mast cells and airway epithelial cells (Beck, 1999). Nitric oxide (NO) is a smooth muscle relaxant and can be a mild bronchodilator  60  when inhaled by humans (Beck, 1999). The role of prostaglandins and N O in regulating airway function is not completely understood and more research is needed to establish their role in the management of EIA (Beck, 1999). It is well known that asthma can be thermally induced as cold, dry air intensifies symptoms (McFadden et al., 1992). The exact physiology of asthma is difficult to understand and it is hard to identify a single cause (Nastasi et al., 1995). Exercise-induced asthma Exercise-induced asthma (EIA) refers to the transient increase in airway resistance that is triggered by vigorous exercise (Nastasi et al., 1995). It can also be defined as a 10% reduction in pre-exercise values of peak expiratory flow rate (PEFR) or forced expiratory volume in 1 second (FEVi) when compared with post-exercise values (Anderson et al., 1975). The symptoms of EIA are not always obvious and may get reported as a cough or being out of shape (Nastasi et al., 1995). This leads to problems with undiagnosed EIA and may cause the avoidance of exercise due to discomfort at a young age and then leading to a sedentary lifestyle. The decline in pulmonary function testing classically occurs 3 to 12 minutes after strenuous exercise (Shapiro et al., 1984). Exercise-induced symptoms in patients with asthma have been found to have a prevalence rate of 40-90%) (Jones et al, 1962). 40-50%) of persons with allergic rhinitis have EIA (Decotis et al, 1980). 8% of 12 year-old children have EIA, and 12 to 23 % > of middle and highschool adolescents have EIA (Burr et al, 1989). Rupp and associates (1993) screened 1241 high school athletes for EIA. Through family history 86%> were identified to be at risk for EIA but only 14%> were identified at risk by way of pulmonary function tests. Aerobic fitness and good conditioning have  61  been shown to benefit patients with EIA (Nastashi et al., 1995). Exercise training helps subjects take advantage of the initial exercise bronchodilation (Haas et al., 1985). The amount of ventilation in exercise is directly related to the intensity of the exercise stimulus. This means that any exercise can lead to EIA if done at a high intensity for a specific duration of time, as this leads to increases in the amount of air being inhaled (Tan et al., 1998). Competitive athletes have very high incidence of respiratory symptoms even when EIA is not present (Storms, 1995). Of the elite athletes studied 40% had coughing, 40%) of chest congestion, 36% of chest tightness and 25% had wheezing following a vigorous exercise bout (Storms, 1995). This suggests that elite athletes have high incidence of respiratory symptoms and this may be related to intensity and frequency in which they train (Rundell et al., 2000). At the 1998 Winter Olympics in Nagano, 17 to 23%> of athletes were diagnosed with asthma. Some sports, such as cross-country skiing had incidence rates as high as 50%>. Asthma was more prevalent in the female Olympians. Chen and Horton (1977) believe that respiratory water loss is important to explain the onset of EIA, whereas Deal and associates (1979) attributed EIA to respiratory heat loss. While the mechanisms of EIA still remain unclear, it is accepted that cooling and drying of the airways associated with increased ventilation represents the cause of postexercise bronchoconstriciton (Ienna et al., 1997). Different types of exercise can be less asthmogenic. Activities done in warm humid environments, such as swimming are less likely to cause an asthma attack when compared to outdoor cold weather activities such as running, cycling and cross-country skiing (Ienna et al., 1997). It is also known that an  62 asthmatic can tolerate intermittent running (Morton et al., 1992) such as soccer and basketball better than continuous exercise bouts (Anderson et al., 1975). The greatest amount of airway obstruction occurs with intense exercise bouts between 60 and 85% of maximal oxygen uptake for 6-8 minutes and closer to 80 to 85% (Silverman et al., 1972). With exercise intensities greater than 60 and 85% of VO2 max post-exercise bronchoconstriction seems to diminish, especially when the duration is longer than 6 to 8 minutes. A warm-up at 60% of maximal oxygen uptake for 15 minutes in duration helps to protect the airways of an asthmatic from bronchoconstriction (McKenzie et al., 1994). Exercise-induced asthma seems to be less prevalent during cycling when compared to running. Running involves negative work, which might account for the reported differences. It is important to note that improved fitness levels have been shown to reduced the severity, duration and frequency of attacks (Haas et al., 1985).  Diagnosis a)  Pulmonary Function Test (PFT) Asthma can be defined as the decreased ratio of F E V i to forced vital capacity  [FEVi/FVC]. Diffusion capacity is usually normal and the airway obstruction is reversible. Spirometry should be used in the initial assessment of patients with suspected asthma. Obstruction in the upper expiratory phase is apparent when the F E V i curve appears "scooped" or "curved" rather than the smooth continuous line seen in normal subjects. Abnormalities in pulmonary function are measured by airflow limitation (Lemanske et al., 1997). F E V i , PEF, F E V i / F V C are reduced in an acute attack. Other abnormalities in lung volume include a decrease in F V C and an increase in functional residual volume, total lung capacity and residual volume (up to 300% to 600% or  predicted normal value) during an acute attack. There will be decreased compliance of the small airways and increased airway resistance (Crapo, 1994).  b)  The Methacholine Challenge Test (MCT) The methacholine challenge test is one of the gold standard tests for the diagnosis  of asthma (Malo et al., 1983). Methacholine is a synthetic derivative of the neurotransmitter acetylcholine, this occurs naturally in the body. Aerosols are administered using a Wright nebulizer attached to a facemask, calibrated to deliver the aerosols at a rate of 0.13 mL-min" . Aerosols are then inhaled for periods of 2 minutes 1  followed by 30 and 90 second F E V i determinations. After a baseline F E V i is established with saline, methacholine is inhaled in doubling concentrations (0.125, 0.25,0.5, 1.0, 2.0, 4.0, 8.0 and 16.0 mg-mL"') every 5 minutes (Juniper et al., 1991). F E V i is measured every 30 and 90 seconds after each concentration until a fall in F E V i of 20% (PC20), compared to the saline control, if a concentration of 16 mg-mL" is reached, this indicates 1  a negative diagnosis of asthma. The percentage fall in F E V i is calculated from the lowest F E V i after each methacholine inhalation and the PC20 is determined by using the following equation: P C = antilog [log C l + (logC2 - log C D (20 - R D ] 2 0  R2-R1 Where:  C l = second last concentration ( <20%> F E V i fall) C2 = last concentration (>20% F E V , fall) R l =% fall F E V i after C l R2 = % fall F E V i after C2  A PC2o<_8 mg-mL" indicatives a positive diagnosis of asthma (Malo et al, 1983). 1  Prescribed inhaled bronchodilators should be withheld for 12 hours prior to the test, however subjects on inhaled steroids should be allowed to continue taking their  64 medication in regular doses. Following the test, a bronchodilator is given to the subject to reverse the effect of the methacholine.  c)  Eucapnic Voluntary Hyperpnoea (EVH) The International Olympic Committee Medical Commission (IOC-MC) has stated  that to use pVagonists at the last winter games, that an athlete must demonstrate that they have asthma. In Salt Lake City 2002, eucapnic voluntary hyperpnoea (EVH) test was used to confirm that an athlete has exercise induced asthma (EIA) (Anderson et al., 2001). In this test the athlete must hyperventilate dry air that contains 5% carbon dioxide at room temperature for a total of 6 minutes at a target of ventilation of 30 times the athlete's forced expiratory volume per second (FEVi). A reduction of F E V i of 10% of more from the baseline value indicates a positive asthma diagnosis. F E V i should be measured after the E V H challenge test and then again in recovery at 3, 5, 10, 15 and 20 minutes. The test requires no short acting bronchodilators be taken eight hours prior to testing, and no long acting bronchodilators of antihistamines be taken 48 hours before testing. The response is classified as mild when the fall in F E V i is 10 and 19.9% when the ventilation is 60%> maximum voluntary ventilation ( M W ) .  A moderate diagnosis is  defined as a fall between 20 and 29.9% in F E V i . The response is severe when the fall in F E V i is 30%o or more at any level of ventilation or if a fall greater than 10%> occurs at a ventilation rate less than 30% M W (Anderson et al., 2001). An E V H or a field exercise challenge may be the best for confirming EIA in athletes. E V H is believed to be the superior test, it is specifically designed to identify exercise-induced bronchospasm and the test can be modified to reproduced symptoms in athletes. E V H tests have been done in thousands of subjects and the reliability is high as it successfully induces  65 bronchoconstriction. For this reason it is necessary to have supplemental oxygen and bronchodilators on hand at the time of testing. Exercise-induced arterial hypoxemia (EIAH) and asthmatics Exercise-induced arterial hypoxemia is thought to result from hypoventilation, ventilation-perfusion inequality and/or diffusion limitation (Dempsey et al., 1999). While it is generally accepted that the pulmonary system does not limit VO2 max in healthy subjects, elite athletes seem to be the exception to this rule. Elite athletes exhibit EIAH and the exercise-induced imperfections in the pulmonary system limit VO2 max- Although a number of studies agree that EIAH is clearly demonstrated in this population the explanation for E I A H is unclear (Powers et al., 1993). Endurance athletes that demonstrate severe EIAH at sea level show even greater signs of desaturation at altitude. It has now been well established that 40 to 50% of highly trained male endurance athletes develop EIAH at near maximal work rates (Powers et al., 1993). It seems likely that V A / Q inequality and pulmonary diffusion play a major role in EIAH, although the physiological mechanism of EIAH remains highly debated. Currently no data exists on the prevalence of EIAH and asthma. EIAH studies are also lacking in female populations. Research is needed to find the incidence rate of E I A H and whether EIAH is correlated with gender, fitness and severity of asthma. This might give better insight to understand the mechanisms involved with E I A H in healthy subjects and elite athletes. Menstrual cycle and respiratory function There have been a number of studies that have reported the role of hormonal influence with respect to airway function. Minute ventilation, maximal exercise response  66 and respiratory drives are increased with higher progesterone levels associated in the luteal phase (Frankovich and Lebrun, 2000). Eumenorrheic athletes showed no changes in exercise performance when compared to nonathletes who demonstrated greater perceived exertion and decrease in maximal exercise response during their luteal phase (Schoene et al., 1996).  One retrospective study reported a fourfold increase in asthma  patients presenting in hospitals during their perimenstrual interval (Skobeloff et al., 1996). During the luteal phase, asthma symptoms have been found to increase and morning peak flows decrease (Pauli et al., 1989). It seems that there is a link between the sex steroids and airway function. More studies need to be conducted on women with exercise-induced asthma. Further research needs to be conducted with regards to asthma diagnostic test (EVH, E C T and MCT) and the phases of the female hormonal cycle. It seems apparent that menstrual phase needs to be controlled when testing eumenorrheic women subjects.  History of exercising asthmatics Exercise is an accepted therapeutic agent in the management of EIA (Fitch, 1986; Tan et al., 1998). Research has documented physical gains in children following exercise-training programs (Fitch, 1986). Asthmatics can be involved in a wide variety of sports at very high levels due to advances in medications used in the management of this disease. In 1984 the Olympic committee noted that when 597 US athletes were surveyed 67 (11.2%) of these athletes confirmed having EIA (IOC, 1984). Endurance athletes such as cyclists and runners had the highest prevalence, EIA was only found in 29 events at the 1984 Olympic Games. Only 26% of these athletes had previous history of asthma. Forty-two athletes had reported coughing, chest tightness, and wheezing after  67 maximal exercise bouts. Forty-one medals were awarded to athletes that demonstrated EIA and 15 of these medals were gold (Nastasi et al., 1995).  Pharmacological agents Asthmatics have a decreased P-adrenergic response (Meltzer, 1991). p 2  adrenergic agonists such as salmeterol and sambutamol work to cause relaxation of the smooth muscle in the lining of the respiratory tracts. A p agonist activates the enzyme 2  adenylate cyclase, causing the formation of a second messenger, cyclic AMP. Intracellular cyclic AMP activates protein kinase A, which causes a reduction of the calcium dependent coupling of actin and myosin, this cause the relaxation of bronchial smooth muscle. p -adrenergic agonists should be used 15 minutes before exercise 2  (Nastashi et al., 1995). The most traditional agents used for the prevention of EIA are inhaled bronchodilators, and have been found to be effective in 80 to 90% of patients with EIA. Salmeterol has been shown to protect against EIA through bronchodilation and has been proven better in terms of duration of action (Anderson et al., 1991). Cromolyn sodium and nedocromil sodium are effective second-line agents (Nastashi et al., 1995). Inhaled steroids used just before physical activity have not been proven effective in the prevention of EIA (Konig et al., 1974). Waalkens and colleagues (1993) found that in long-term inhaled budeosonide by 55 children, the incidence rate of EIA was reduced by 33% and the severity of the disease decreased by half. Inhaled corticosteroids will reduce the exercise asthma response by reducing the state of inflammation in the airways (Beck, 1999). The IOC and many other collegiate associations have been involved in mandatory drug testing, as a number of drugs used in the management of EIA are banned. This has major implications to the athlete with EIA  68 (Nastashi et al., 1995). For the most part, these drugs fall into the performanceenhancing category (Nastashi et al., 1995). Effect of EIA on exercise performance If asthma is well-controlled, then asthma does not usually limit exercise performance (Freeman et al., 1990). Asthmatics have the same exercise response as normal subjects when free from attack. In a study by Packe et al. (1987) 10 untrained asthmatics and 10 matched controls exercise at 85% of maximal oxygen uptake. No difference was found between the two groups with respect to VO2, V E , and SaC>2. Respiratory exchange ration was higher is asthmatic subjects. There is a general improvement in airway function during short-term exercise, and exercise performance in laboratory conditions has been normal even without the use of medication before the exercise stimulus (Ienna and McKenzie, 1997). It is not known if laboratory conditions are similar to regular exercise in field conditions (Beck, 1999). Interval exercise with a prolonged constant load has been shown to cause more bronchoconstriction and this could limit exercise performance (Beck, 1999). If baseline lung function is reduced and not corrected before the onset of exercise, the maximal ventilatory capacity could be decreased and the exercise performance compromised (Freeman et al., 1990). Conclusion Asthma can occur due to a number of complex factors such as viral respiratory infections, allergen exposure and withdrawal from medications. The severity of the asthma attacks will indicate which treatment should be administered. Acute, severe exacerbations of asthma are potentially life threatening and require critical medical assessment and therapy.  69  Asthmatic airways are populated by more inflammatory cells, when compared to normal airways. During exercise asthmatic airways will lose water due to inhaling dry air, this increases the net osmotic pressure of the airway fluid and causes mast cells to degranulate and release mediators such as histamine, leukotrienes and prostaglandins (Beck, 1999). Increasing the exercise intensity and ventilation is known to partially reverse the bronchoconstrition. During constant load exercise, bronchoconstriciton develops after approximately 15 minutes (Beck, 1999). After exercise ventilation returns to normal, bronchodilation is reduced and bronchoconstrition develops (Beck, 1999). There are many unanswered questions regarding EIA. Most asthmatics can complete exercise without bronchoconstriction, in some asthmatics bronchoconstriction does occur and this is known to limit exercise performance. Exercise-induced asthma is a significant problem for children and young adults. Uncontrolled symptoms may not only limit performance but cause exercise avoidance. Proper diagnosis and prevention is the main approach for the management of EIA. Long-term exercise and aerobic fitness play a major role for patients with EIA for attainment of full physical potential. It seems apparent that asthma is highly related to inflammation. Elite athletes have higher than normal incidence of respiratory symptoms. These asthma-like symptoms are thought to be related to intensity and frequency of training. Although it may also be due to lung damage due to the inflammatory response. Understanding exercise immunology in patients who suffer from asthma is an area that needs to be addressed.  70 Appendix B: Review of the Literature: Exercise and immunology Introduction The pulmonary system is designed to influence oxygen delivery via its central role in gas exchange and left ventricular preload. The vascular bed of the lung responds to a number of biomechanical and biochemical stimuli and similarly is susceptible to inflammatory stress. The endothelium of the lung is the largest endothelial surface in the body and functions as the critical middle structure between environment and the body. As a barrier it functions to transform humoral signals, initiate inflammatory response and plays a role in vascular injury, repair and remodeling. When conditions of increased blood flow are present, pulmonary endothelial dysfunction could alter vascular tone, impair blood-gas diffusion, permit interstial edema, cause ventilation-perfusion mismatch, and promote arterial hypoxemia (Wetter et al., 2002). Pulmonary endothelial activation may be due to chronic or otherwise increased lung blood flow, and this may contribute to gas exchange impairment seen in some elite athletes at submaximal workloads. The ventilation-perfusion ( W Q ) matching and diffusion depends highly upon airway, blood distribution and vascular structure, and this has been attributed to exercise-induced arterial hypoxemia (EIAH) (Dempsey et al., 1999). EIAH will be discussed in the upcoming review of literature. Overview of the immune system The immune system developed from means of self-identification, by distinguishing the body's own cells from those originating outside the body, it also has a homeostatic mechanism (MacKinnon, 1999). The immune system is very complex and capable of recognizing and defending the body against a large number of irritants from  71 the external environment. The immune system covers the body's responses to the foreign molecules, usually called immunogens; microorganisms including viruses, bacteria, fungi, and parasites; tumor growth; cell and tissue transplantation; and allergens. It responds to these foreign bodies by coordinating various diverse cells, tissues, and messengers molecules throughout the body (MacKinnon, 1999). General structure of the immune system The immune response begins when an invading foreign body penetrates the chemical and physical barriers protecting the body. The pathogen meets and is engulfed by phagocytes, which kill the microbe and degrades its protein. Specialized immune cells, called T-helper lymphocytes recognize and are activated by presentation of the foreign protein on the phagocyte's surface. Helper T cells stimulate other important immune cells to help with the microorganism. During the initial encounter memory Band T-cells respond quickly to the infection. There are two immune systems; innate immunity and adaptive immunity, since the adaptive system requires a few days to become fully activated, the innate system provides an essential first line of defense from the early stages of infection. Adaptive immunity is involved later, and involves the actions of specialized immune cells (MacKinnon, 1999). General features of inflammation The inflammatory process is closely linked with the process of repair (Collins, 1999). Inflammation destroys and dilutes the infectious agent, but it starts a series of events to heal and reconstruct damaged tissue. Inflammation is fundamentally a protective mechanism in which it aims to ultimately rid the organism of both the initial cause of cell injury and the consequences of such injury (Collins, 1999). The  inflammatory response occurs in the vascularized connective tissue, including plasma, circulating cells, blood vessels, and cellular and extracellular constituents of connective tissue (Collins, 1999). The circulating cells include neutrophils, monocytes, eosinophils, lymphocytes, basophils and platelets. These cells will be discussed in further detail in the following sections. Inflammation and the inflammatory response to exercise Leukocytes are involved in virtually all aspects of immune function, either directly via cellular activities or indirectly via release of soluble factors. Exercise causes profound changes in the number of circulating leukocytes. Although even brief exercise may increase leukocyte number in the circulation, leukocyte number usually returns to baseline levels within most types of exercise, the exception to this is exercise that lasts more that 24 hours (MacKinnon, 1999). The selectins mediate leukocyte rolling, while sticking and diapedesis depend on the interaction between leukocyte integrins. Each of these adhesion molecules is regulated by cytokines, platelet activating factor, and leukotrienes (Ward, 1997). Strenuous exercise incites an acute inflammatory response, marked by leukocytes and neutrophil activation (Weight et al., 1991). Cells of the immune system in relation to exercise will be discussed in the next section. Leukocytes Leukocytes, or white blood cells are immune cells found in several lymphoid organs and tissues throughout the blood and lymph system of the body (MacKinnon, 1999). They originate from stem cells in the bone marrow and then undergo further maturation and differentiation in the thymus and the bone marrow. They interact with  73  other cells and foreign bodies in the lymph nodes, spleen and in the stomach. Leukocytes migrate between different lymphoid tissues via the circulation and the lymphatic system. Leukocytes are comprised of granulocytes, monocytes and lymphocytes. Many of these cells surface proteins have specific functions, such as receptors or adhesion molecules. Adherence of leukocytes, and neutrophils are key to immune defenses and the inflammatory response. The rolling and sticking of cells in pulmonary arterioles and venules and retention in alveolar capillaries is dependent on lung inflation and adhesion molecules (Collins, 1999). As cardiac output increases there is an increase in microvascular blood flow and a reduction in leukocytes and endothelial interaction (Kuhnle et al., 1995). Lien et al. (1990) found that transit times of fluorescently labeled neutrophils in pulmonary capillaries fell in a lung of a dog when given epinephrine and also under hypoxic conditions. There has been conflicting evidence for exercise and certain cells, but the research points out that other factors may be responsible for neutrophil transit time in the pulmonary circulation rather that local velocity flow (MacNee and Selby, 1993). Cortisol may be responsible for neutrophilia and lymphopenia after prolonged intense exercise (Pedersen et al., 1997).  Cytokines Cytokines are polypeptides that are involved in communication between lymphoid and other cells (Liles et al., 1995). They are low-molecular-weight proteins that are secreted by white blood cells and a variety of other body cells in response to a number of inducing stimuli. Cytokines function as intercellular messenger molecules that evoke particular biological activities after binding to a certain receptor on a target cell (Pedersen et al., 1998). Interleukins, growth factors, TNF-a, interferons and chemokines  74  are all classified as cytokines. The term cytokine refers to the general class of regulatory factors, which includes lymphokines, and monokines (MacKinnon, 1999). Cytokines are produced at the site of tissue injury. Cytokines are regulatory growth factors although they function in other ways, and are mediators of the inflammatory response. Cytokines are involved in virtually every aspect of immune function and can act on other nonimmune cells (MacKinnon, 1999). Cannon and Kluger produced the. first research on cytokines in 1983, they showed that plasma obtained from humans after 1 hour of cycling at 60% VO"2max elevated rat rectal temperature. Plasma obtained before strenuous exercise failed to produce the same results (Cannon et al., 1983). Cytokines are released following eccentric exercise by immunoregulatory proteins to promote local repair (Pedersen et al., 1997). Cytokines have also been present after concentric exercise (Pedersen, 2000). The magnitude of increase is related to intensity and duration of the exercise bout (Pedersen, 2000). Regulation by anti-inflammatory cytokines and receptor antagonists maintains the protective effect of these immune proteins, but failure of homeostasis disrupts the balance, and allows proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin, IL-6 and IL-8, to cause tissue injury through the promotion of neutrophils (Bone, 1996). Increases in plasma levels of IL-1 (3, IL-2, IL-6 and TNF-oc have been present immediately after long-duration intense exercise (Cannon et al., 1983). This depends on eccentric and concentric exercise, gender, intensity of exercise, time of day and the fitness levels of subjects. Sprenger et al., (1992) showed significant elevation in urine of IL-1 (3, IL-2R, IL-6, T N F - a and IFN-y, following a 20kilometre run. Cytokines may prove to be a more sensitive marker of exercise-induced immune dysfunction (Northoff et al., 1994), but may interfere with exercise measures.  75  Characteristics of the IL-6 response to exercise IL-6 is a cytokine and is produced locally in the skeletal muscle and is known to have growth factor abilities and is said to be a key immune mediator in an inflammatory response. IL-6 is expressed by a variety of normal and transformed cells. Cytokines facilitate an influx of lymphocytes, neutrophils, and monocytes, which help in the clearance of the antigen and ultimately aid in healing (Pedersen, 2000). Northoff and Berg were the first researchers to suggest that IL-6 may be involved in the generation of the acute phase response after exercise (Northoff et al., 1991). They found IL-6 to be increased by 100-fold after a marathon run (Northoff et al., 1991) (levels did not exceed 100 pg.rnL). IL-6 levels have been shown to increase significantly 30 min after the start of running and peak after 2.5 hours of running (Ostrowski et al., 1998). IL-6 has been measured at several time points during a run and studies have found that they rapidly decline at the end of exercise (half-life of 1-2 hr) (Pedersen, 2000). Since they have such short half-lives, the time points in which the samples are collected can influence the results (Pederson et al., 1997). IL-6 levels seem to peak 1 - 1.5 hr after prolonged eccentric one-leg exercise. IL-6 levels seem to differ between exercise mode that induce early muscle damage and activities that cause a later onset of muscle damage and also the training status of the subjects (Ostrowski et al., 1998). 56 runners were tested from the Copenhagen Marathon in 1996 to 1998 and research suggested that runners with the fastest running times were found to have the highest IL-6 levels (DeRijk et al., 1994). IL-6 is associated with muscle damage using an eccentric exercise modeal (Bruunsgaard et al, 1997). Muscle biopsies taken after intense exercise all support the idea that during eccentric exercise myofibers are mechanically damaged and this process stimulates local  76  production of inflammatory cytokines (Pedersen et al., 1998). IL-6 is the type of cytokine that is produced in the largest amounts in response to exercise. It is evident that IL-6 plays a beneficial role and may be involved in mediating exercise-related metabolic changes (Pedersen, 2000). The increase in IL-6 is tightly related to the duration of the exercise.  Cell adhesion molecules Adhesion molecules mediate binding between cells or between cells and extracellular matrix proteins. They are displayed as membrane or transmembrane proteins on the cell surface (MacKinnon, 1999). Adhesion molecules play a key role in mediating leukocytes within the circulation to lymphoid and other tissues, and importantly to the sites of inflammation or infection. There are four types of cell adhesion molecules: selectins and vascular addressins, which are important for leukocyte homing to a specific site, integrins, which help binding between cells and extracellular proteins, and Ig super-family which are key to antigen recognition and T-cell activation (Janeway and Travers, 1996). Seletins are a family of cell adhesion molecules with an extracellular lectin-like binding site. They are expressed on the surface of leukocytes, platelets and endothelial cell and have been named accordingly: L-selectin, P-selectin and E-selectin. P-selectin is stored within Weibel-Palade bodies of the endothelial cells and the a-granules of platelets. P-selectin can be expressed quite rapidly and is expressed on the surface of stimulated platelets. E-selectin is synthesized by cytokine-activated endothelial cells and requires several hours for expression. P-selectin promotes the initial localization of leukocytes and platelets at sites of the inflammation, E-selectin enhance recruitment of leukocytes (Rubin, 1990). During resting conditions, selectins mediate  77  only weak binding to complementary adhesion molecules on the endothelium, allowing leukocytes to roll along (MacKinnon, 1999). During inflammation, dilation of blood vessels in the affected sites slows blood flow and leukocyte movement, this causes more interaction between selectins and addressins. This allows leukocytes to adhere to the endothelium, allowing leukocytes to squeeze between the endothelial cells in the vessel and migrate to the infectious tissue. Elevated plasma levels of adhesion molecules E - and P- selectin have been found in acute lung injury and have been used as indirect markers of endothelial activation or injury. Baum et al. (1994) found that soluble ICAM-1 (CD54) was elevated by 20% following an endurance-training program in middle-distance runners. Tilz et al. (1993) saw a 23% increase after a roundtrip ascent and descent from 750m to 2350m over a fivehour period in eighteen untrained males. In contrast, Jilma et al. (1997) reported a < 11% rise in sICAM-1 soluble VCAM-1 (CD 106), and soluble E-selectin (sCD62E) in twelve untrained men after a maximal cycle ergometry and sixty minutes at 60% VC^maxHowever this was not clinically significant as there was 8% variability. Eldridge et al. (1998) reported significantly increased levels of sE-selectin at altitude (3810 meters). Selectins rose from 28.7 +_8.9 ng-mL pre-exercise; 39.4 + _1  ng-mL" 24-hours post-exercise, p<0.05, in 5 subjects who exercised at 85% V 0 2 xfor 1  ma  three 5 minute intervals with a 5 minute recovery at 30% VO"2max between. This implies alveolar-capillary structural failure with exercise at altitude, but the contribution of exercise alone cannot be determined, and this may not occur at sea level. The pulmonary endothelium was disrupted with exposure to altitude in a hypobaric hypoxic condition, there were increased levels of plasma E-selectin in 6 subjects with hypoxemia, acute  78  mountain sickness (AMS) and 8 climbers with high altitude pulmonary edema (HAPE) that were treated at a medical camp at 4200 meters (Grisssom et al., 1997). Plasma E selectin levels increased significantly in 17 subjects on ascent from sea level to 4200 meters, and were significantly higher compared to sea level control values. Significant correlations were seen between plasma E-selectin and the degree of hypoxemia. Plasma P-selectin levels were unchanged on ascent to altitude in subjects with either A M S or H A P E (Grissom et al., 1997). Hunte et al. (unpublished data) measured plasma levels of in fourteen habitually active, eumenorrheic female subjects before and after an incremental maximal cycle test during the follicular stage of their menstrual cycle. Plasma concentrations of soluble E-selectin were not significantly different before or after exercise, but plasma concentrations of P-selectin rose significantly. Some of the research demonstrates elevation in both E - and P-selectin and other studies fail to show any difference. The evidence remains controversial for the presence of endothelial selectins. There seems to be elevated levels of E - and P- selectin following exercise, however the mechanisms are not yet clear. Influence of gender and fitness Immune responsiveness is much greater in women than men and may account for the greater susceptibility to autoimmune disease in females (Ahmed et al., 1985). Leukocytes subpopulations are present and vary over the normal menstrual cycle. Monocytes and neutrophils were significantly higher in the luteal phase of the menstrual cycle (Mathur et al., 1979). Moyna et al., (1996) found that increased production of IL-1 was independent of gender and fitness in a group of 64 sedentary and moderately fit males and females following 6 minutes of intervals at 55%, 70% and 85% of V02max.  79  Acute lung injury Acute lung injury is described by the clinical features associated with increased capillary-alveolar permeability, alveolar damage and severe gas exchange impairment and this may be an important consideration for individuals with asthma. Elevated levels of von Willebrand factor (vWF:Ag) have been reported in patients with acute respiratory failure (Carvalho et al., 1982) and were predictive of acute lung injury in patients with nonpulmonary sepsis (Rubin et al., 1990). In view of their central role in neutrophil-mediated lung injury, soluble vascular selectins have also been measured as indirect markers of endothelial activation or injury. E-selectin is produced exclusively by endothelium following cytokine activation, whereas P-selectin is performed and stored in a granules of platelets or in company with vWF:Ag in endothelial Weibel-Palade bodies (Collins, 1999). For 17 patients with positive blood cultures, plasma levels of sE-selectin were elevated in those with septic shock but not bacteremia without hypotension (Newman et al., 1993). Levels of sE-selectin were elevated in 25 patients with severe sepsis compared to healthy volunteers (Kayal et al., 1998). Research has failed to find a role to monitor disease in critically ill patients with acute lung injury. The role of inflammation and E I A H The role that lung inflammatory mediators play in the development of exerciseinduced arterial hypoxemia is not well known. It has been suggested that the physiological consequences of strenuous exercise may be similar to that of acute response of inflammation. Inflammatory mediators have been found in athletes before and after strenuous exercise. This indicates that acute and chronic exercise may cause an increased  80  inflammatory response. There is an increased incidence of asthma in high-level athletes (Larsson et al., 1993) and airway inflammation and remodeling in nonasthmatic athletes (Karjalainen et al., 2000) indicating that individuals with chronic high levels of exercise training may develop asthma-like conditions. Wetter et al. (2002) looked at the role of lung inflammatory mediators as a cause of EIAH in 9 male and 8 female subjects, all subjects were healthy young athletes (age 23 ± 3 yr) and had a wide range of severities of EIAH. They hypothesized that mismatch and diffusion limitation is the development of mild interstitial pulmonary edema caused by high-pulmonary pressure and vascular leakage due to inflammatory leakage. Lung function, arterial blood, gases and inflammatory metabolites in plasma, urine and sputum were assessed during treadmill running after the administration of fexofenadine, zileuton, and deocromil sodium or a placebo. The results showed that drug administration did not improve EIAH or gas exchange during intense exercise. Oxygen consumption and ventilation were unaffected by drug treatment. Post-exercise sputum showed no significant difference in inflammatory markers. The authors concluded that airway inflammation is insufficient to cause gas impairments and does not appear to be linked to EIAH in healthy young male and female athletes (Wetter et al., 2002). Rivier et al., (1994) examined the effects of strenuous exercise on the release of cytokines. Ten male, endurance trained young athletes and 6, endurance trained master athletes performed an incremental cycle test to exhaustion. Blood samples were taken before and after exercise and 20 minutes following the maximal cycle test. Mean oxygen saturation was significantly decreased in the young athletes and the master athletes. The spontaneous release of T N F - a and IL-6 was significantly increased in the young athletes  81  compared to the master athletes. When all subjects were considered together IL-6 was significantly increased at the end of exercise and slightly but not significantly decreased during the post-exercise recovery. There was a significant correlation between spontaneous IL-6 release in vitro and maximal power. There was no correlation between the release of IL-6 and T N F - a and lung function measured during hypoxemia. They concluded that it could not be confirmed that these inflammatory mediators play a role in hypoxemia.  Conclusion Faced with the stress of exercise, and particularly the repetitive and sustained increases in ventilation and blood flow seen in habitual aerobic athletes, it is perhaps more remarkable that every aerobic athlete does develop exercise-induced arterial hypoxemia. These differences in the prevalence and development of exercise-induced arterial hypoxemia may exist due to inter-subject variability and the reasons for these mechanisms remain unanswered. The understanding of the immune and cellular processes, and how these systems are affected by exercise remain unknown. Endothelial dysfunction is an early feature of acute lung injury. Elevated cell-specific plasma markers of cellular adhesion molecules have been detected in patients with acute lung injury. It therefore seems important to understand the role these immune cells play in respiratory diseases, this is particularly key to patients that suffer from asthma.  82 Appendix C : Review of the Literature: Exercise-induced arterial hypoxemia Introduction The lungs' capacity for maintaining oxygen homeostasis during exercise is a question that has long puzzled exercise physiologists. It has recently been stated that the structural components of the lung seem to be over-built when examining the need for pulmonary O2 transport in the healthy untrained human during maximal exercise at sea level (Harms et al., 1998). Pulmonary gas exchange has not been thought of as the limiting factor for oxygen uptake in healthy individuals. This is not always the case as exercise-induced arterial hypoxemia (EIAH) commonly occurs in elite athletes reaching maximal work values (Powers et al., 1993). EIAH can be defined as a decrement in PaC>2 of greater than 1.3 kPa (10 Torr) below resting values (Dempsey et al., 1984). The capacities of the lungs, airways, and chest walls do not always exceed the stresses of maximal exercise in some trained athletes (Harms et al., 1998). It has been reported in a number of studies that young male athletes, with maximal oxygen consumptions of >150% of normal, show exercise-induced arterial hypoxemia and airflow limitation during maximal exercise (Powers et al. 1992). Elite athletes may exhibit the inability to maintain arterial oxygenation due to training increases in maximum O2 consumption secondary to cardiovascular and skeletal muscle adaptations (Dempsey et al., 1984). During maximal exercise PaC>2 values may drop 18 to 38 mm Hg below resting values for some elite athletes (Dempsey et al. 1984, Powers et al, 1992), and SaC^by as much as 15% below resting values (Dempsey et al. 1999). Dempsey et al. (1999) contend that EIAH does occur in a number of healthy fit subjects during exercise at sea level  83 (Dempsey et al. 1999), and is prevalent in highly trained subjects exercising at extremely high levels of metabolic work (Dempsey et al., 1984). E I A H was first described in 1958 (Holmgren, 1958), and presently discussions regarding E I A H still exist. Rowell et al. (1964) demonstrated that %Sa0 declined from 2  a normal resting 98% to 85%) during maximal exercise in endurance trained male athletes. Gledhill et al. (1980) agreed with this study but found that there was a decrease of 22 mmHg in Pa0 from resting values during heavy exercise in endurance athletes. 2  Dempsey et al. (1984) disagreed with the past literature and concluded that E I A H was not an isolated case, and the decrease in values were dependent on the individual subject (Dempsey et al., 1984). This study examined 17 male elite endurance athletes exercising at high intensities. EIAH was reduced in 8 of these athletes from 21 to 35 mmHg below normal resting values (Dempsey et al., 1984). When evaluating EIAH data it is important to note the type of pulse oximeter used in the investigation; only studies that use exercisevalidated pulse oximeters should be considered as compelling evidence to prove or disprove that E I A H occurs in the population in question (Powers et al., 1993). Incidence of exercise-induced arterial hypoxemia in endurance athletes It has been demonstrated and concluded that severe EIAH occurs in healthy male subjects with very high V 0  2m a x  values. It should be noted as well that this is not  universal among all elite endurance athletes (Williams et al., 1986). It is important to define E I A H when discussing the incidence of occurrence. Dempsey and Wagner define E I A H as mild E I A H can be defined as an arterial 0 saturation of 93-95% (less than 32  4%> of rest), moderate EIAH as 88-93%, and severe E I A H as less than 88% (Dempsey et al., 1999). Powers and colleagues (1993) define EIAH as a reduction of 18 mm Hg less  than resting values and from this definition of EIAH Dempsey et al. ( 1 9 8 4 ) reported between 40 -47% of endurance athletes developed EIAH !  (V0  2 m  ax68  ). During an incremental treadmill test Dempsey and colleagues  to70 mL-kg'-min"  (1984)  tested 17 male  aerobic athletes. Eight of the 12 athletes demonstrated reductions in P a 0 of 2.8-4.7 kPa 2  (21-35 Torr) (Dempsey et al.,  1984).  Powers et al. (1988) and Martin et al. (1992)  reported that when EIAH was defined as less than 4% of resting the resting value, between 46 and 52% of elite athletes tested exhibited EIAH during high work loads. Varying but similar degrees of impairment in %Sa0 have been demonstrated in the past 2  literature (Rice et al., 1999). The literature seems to be conclusive that EIAH is present in between 40-50% of endurance athletes and this does not differ between cyclists and runners. No data exist in other endurance sports such as cross-country skiing or swimming and there is a lack of data for female endurance athletes (Powers et al., 1993). Even though E I A H values are highly reproducible is seems important to note that very few studies used temperature corrected arterial blood gas variables and most of the sample sizes for blood gas measures were very small. The prevalence of EIAH will likely vary with such factors as age, gender, and certainly the numbers and methods used to study each population (Dempsey et al., 1999). Mechanisms of exercise-induced arterial hypoxemia Hypoxemia during exercise can occur due to a number of factors. Those subjects that experience E I A H seem to have an equal contribution from a widened A - a D 0 and an 2  absence of hyperventilation when compared to subjects that do not experience desaturation (Dempsey et al., 1999). EIAH is believed to result from hypoventilation, venous admixture, diffusion limitation or some combination of the mentioned factors.  Alterations in arterial oxyhemoglobin saturation have a much greater impact on arterial oxygen content and oxygen delivery than changes in PaC>2 (Hunte, unpublished data). Therefore reductions in %Sa02have a potentially greater impact on exercise performance. It seems possible to conclude that those athletes who develop E I A H may be at a performance disadvantage compared to their non-desaturating or less desaturating counterparts. Hypoventilation Hypoventilation is defined as alveolar ventilation under the rate metabolically required to maintain normal arterial blood gas values (Powers et al.,  1993).  This is  reflected in an increase in PaC02 when there is an increase in arterial carbon dioxide. This may be responsible for some of the differences in EIAH between elite athletes (Dempsey et al.,  1984).  During heavy exercise, relative hypoventilation causes a loss of  the driving force for oxygen transfer across the alveoli and into the circulation. It has , been noted that several subjects with EIAH will tend to underventilate during light and moderate exercise bouts (Dempsey et al.,  1999).  Blunted drives to breathe reduces the  ventilatory responses to exercise, but these responses have many exceptions. E I A H is not preventable by simply increasing V A (Dempsey et al.,  1999),  in many of the severe cases  of E I A H the high amount of hyperventilation is not mechanically possible (Dempsey et al.,  1999).  Powers et al. ( 1 9 9 2 ) found no correlation between PaC>2 and PAO2 in athletes  during maximal work. Some investigators do not believe that hypoventilation is an important factor to determine the occurrence of EIAH in athletes (Powers et al.,  1992).  Ventilation-perfusion mismatch Ventilation-perfusion (V /Q) inequality is a mismatching of perfusion and A  ventilation in the lungs, this may result in the impairment of pulmonary gas exchange in certain types of lung disease (West, 1991). The understanding for why it worsens during exercise is unclear (Dempsey et al., 1999). It is possible that the V / Q inequality occurs A  due to variation in airway and vascular resistance. This does not seem to be significant at rest but at exercise there is an increase in gas and blood flow rates and this can alter ventilation and blood flow distribution (Dempsey et al., 1999). For healthy subjects this relationship is generally well matched and does not have an adverse affect on gas exchange during rest (West, 1991). The question remains as to whether the V / Q A  inequality contributes to incomplete pulmonary gas exchange for those athletes who demonstrate EIAH (Powers et al., 1993). Studies using radiotracer techniques suggest that during heavy work, exercise promotes a regional V / Q homogeneity (Bake et al., A  1968). Direct evidence for its contribution to EIAH is lacking. The persistence of V / Q A  mismatch beyond the time required for ventilation (V ) and cardiac output (Q) to return A  to resting levels post-exercise does not support this mechanism (Schaffartzik et al., 1992). The V / Q cannot explain EIAH for those subjects that do not suffer from exerciseA  induced bronchoconstriction, although there is supporting evidence for the role of histamine and the development of EIAH (Prefaut et al., 1997). Several studies have demonstrated that the V / Q mismatch increases during maximal exercise and this A  explains the widening of the A-a DO2 difference (Gledhill et al., 1977). Hammond et al. (1986) showed that the V / Q mismatch increased with exercise intensity up to an oxygen A  87 consumption of 3 L-min" . At elevated work rates the V / Q equality remained constant 1  A  but the A-a DO2 difference increased. A concrete explanation for why V A / Q inequality is different for each individual is unknown. In the 1999 review paper, Dempsey and Wagner presented theories to explain inter-subject differences. There may be underlying structural differences in blood vessels and/or in airways that may become important during elevated flow rate with exercise, although the research does not seem to support this idea (Schaffartzik et al., 1992). Bronchoconstriction and airway secretions may impair ventilation, although the administration of 100% oxygen, lead theories to support circulatory mechanisms (Gale et al., 1985). Ventilation could be altered by mediators of vascular tone and/or perfusion distribution (Anselme et al., 1994). Increased transcapillary fluid flux from enhanced pulmonary blood flow and perfusion pressure could promote accumulation of mild interstitial edema, which collects around bronchioles and could alter compliance and change alveolar-capillary architecture (Hopkins et al., 1998). This is the most plausible explanation because increased extravascular lung water could potentially explain V / Q A  inequality and diffusion limitation and account for V A / Q under hypoxic conditions due to hypoxic vasoconstriction (Wagner et al., 1992). These factors should not be considered exclusively, it is very likely that they collectively contribute to V A / Q during exercise. Venoarterial shunt The circulatory system contains areas where the venous blood is not circulated and thus venoarterial shunt results in poorly oxygenated blood (West, 1995). This poorly oxygenated blood enters into the arterial circulation and causes a decrease in Pa02. Shunts can occur within the lungs or between atria from right to left (Dempsey et al.,  88 1999). The A - a D 0 is accounted for by V / Q inequality, no research exists to support 2  A  diffusion limitations from extrapulmonary shunts (Wagner et al., 1986). The V / Q A  mismatching is greater during heavy exercise than at rest (Wagner et al, 1986). Alveolar ventilation increases relatively more than does cardiac output during exercise and the V / Q inequality is shifted to a higher range of ratios (Dempsey et al, 1999). The A  importance of the venoarterial shunt was tested in an experiment by Dempsey et al. (1984) and Powers et al. (1992); they hypothesized that breathing hyperoxic gas would have limited effect on Pa0 . Subjects were required to switch from breathing a normoxic 2  gas to a hyperoxic gas. Pa0 levels were increased back to normal levels in hypoxemic 2  athletes when working at a near maximal effort. Therefore it can be concluded that the veno-arterial shunt does not seem to play a major role in the development of E I A H (Powers etal, 1993). Diffusion limitation There is a diffusion limitation at or near V 0 max, which is more common in fit 2  subjects and in athletic animals such as dogs and horses (Wagner et al, 1996). Consequently, it is no surprise that most athletic subjects and species are most affected by diffusion limitation, due to high cardiac output (Q). This is a possible explanation for the development of E I A H in endurance athletes. During exercise there is a decrease in the partial pressure of oxygen, mixed venous blood and red blood cell transit time (Powers et al, 1993). Increases in cardiac output can account for the decrease in red blood cell transit time. Human physiology accounts for this by making adjustments; firstly the hyperventilation causes an increase in P A 0 which increases the driving force for the 2  diffusion of oxygen into the blood (Powers et al, 1993). Secondly there is a dramatic  89 increase in capillary blood volume; this increases surface area and allows for more diffusion across the surface (Powers et al., 1993). Subsequently, with these changes no significant problems in diffusion exist with healthy untrained individuals. Dempsey et al. (1984) proposed this was more of an issue with the elite athlete due to the heavier demand placed on the pulmonary system and the high metabolic demands placed on the system during heavy exercise. Dempsey et al. (1999) concluded that it would be unlikely that the veno-arterial shunt or V A / Q inequality could explain the EIAH seen in the 16 highly trained subjects. The development of EIAH in these athletes may be attributed to a diffusion limitation and very short transit time of the red blood cells, when pulmonary blood flow continues to increase (Dempsey et al., 1984). Wagner and colleagues (1986) stated that with an increase in cardiac output there is an increase in pressures in the pulmonary artery, and this may cause a small scale edema and result in an increase in the distance from the alveolar membrane to the RBC (Wagner et al., 1992). High cardiac output is highly correlated with elite athletes, and this can cause even smaller RBC transit time (Powers et al., 1993). There is an increased rate of alveolar and endocapillary gas exchange due to the decreases in PO2 in the venous blood (Wagner et al., 1982). This causes a shift in the oxyhaemoglobin dissociation curve. The RBC transit time is approximately 400 msec. It is important to note that 600msec is the average time required for gas exchange (Dempsey et al., 1987). Hammond and colleagues (1986) concluded that the diffusion limitation exists during heavy exercise in moderately fit subjects. Warren and associates (1991) concluded that decrease in mean transit time could not alone explain the development of  EIAH in male athletes, although pulmonary diffusion limitation could still exist in this population. The influence of exercise duration, intensity, mode and repetition on E I A H The effect of exercise intensity and duration on E I A H E I A H can occur at or near very intense maximal exercise (Powers, 1988; Dempsey, 1999). Subjects displayed the onset of gas exchange at submaximal exercise due to minimal changes in ventilation at the beginning of the exercise bout (Harms, 1998; Rice, 1999). In other trained athletes EIAH can be present at moderate exercise, most likely due to the widening of A - a D 0 with small amounts of hyperventilation 2  compensation (Rice et al., 1999). When EIAH occurred at submaximal work-loads it is consistently associated with sluggish ventilatory responses (Dempsey et al., 1984). These hyperventilatory effects on gas exchange during steady-state exercise appear to prevent E I A H during the transit from rest to work (Oldenburg et al., 1979). The type and duration of an exercise bout will affect EIAH (Dempsey et al., 1999). Dempsey and associates (1984) demonstrated that when fit subjects (susceptible to EIAH) preformed 4 to 5 minutes of heavy exercise, the Pa02fell within the first 30 to 60 seconds of exercise and then was maintained at this decreased level for the duration of the exercise. The percent of Sa02 continued to fall further as a result of the linear decrease in pH. Exercise mode and E I A H The current belief is that treadmill running causes greater decreases in % Sa02 or Pa02 when compared to cycling, due to greater response to ventilatory demand. Gavin and Stager (1999) determined through ear oximeter that %Sa0 during running was lower 2  when compared to cycling. Upright and supine cycling causes the same occurrence of  91 E I A H as does running and graded walking when subjects are at similar V 0  2 m a  x  (Dempsey et al., 1999). Pedersen et al. (1996) compared Pa0 and Sa0 in high aerobic 2  2  power cyclists during recumbent versus upright cycling and although there was no difference in gas exchange between positions, they postulated that if blood flow was determined by gravity, then more homogenous distribution and improvement in V / Q A  matching may be seen in the recumbent position. The results do not support this conclusion. Glenny (1998) seems to believe that this conclusion should be based more on anatomical heterogeneity and not on gravity, as gravity is not the biggest factor that determines blood flow distribution. Moderate prolonged exercise less that 80% of V 0  2  max only rarely causes EIAH and this is thought to occur due to the greater hyperventilatory response (Dempsey et al., 1999). Rice et al. (1999) found that there were significant changes in gas exchange during a treadmill and cycling ergometer test with elite male runners and cyclists. Subjects were required to exercise at 95% of their V 0 a f b r 5 minutes with 90 minutes 2m  X  of rest between randomized tests. Significant differences were seen between treadmill exercise and cycle ergometry in P a 0 (mean +/- SE; cycle 12.0 +/- 0.3 kPa (90.2+/-2.5 2  Torr) versus treadmill; 10.8+/-0.2 kPa (80.8+/-1.8 Torr). No significant differences were seen between exercise modalities in %>Sa0, A-a D 0 or V0 eak. Greater response to 2  2  2p  ventilation during cycling, likely induced in response to a greater lactate and [H+] load, while running may have provoked more V / Q inequality. A  Repeated exercise and E I A H McKenzie and associates (1999) determined no difference between %>Sa0 in 13 2  males athletes measured by ear oximetry when maximal cycling tests were separated by 1  92 hour. Hanel and associates (1997) detected no difference in Pa0 , P a C 0 and %Sa0 2  2  2  when examining two 6-minute maximal rowing ergometer tests that were separated by a 2-hour recovery period. Gas exchange inefficiencies were not seen during maximal exercise tests of the second bout. Caillaud et al. (1996) proved in an experiment similar to Hanel et al. (1997), there were no differences seen in gas exchange, even when maximal cycle tests were only separated by 30 minutes. In a study by St. Croix et al. (1998) 28 female subjects were tested by way of an incremental treadmill test to exhaustion followed by a constant-load maximal treadmill test 20 minutes later. Results failed to show any impairment with gas exchange, there was in fact a reduction in ideal A - a D 0 and increases in P a 0 and %Sa0 compared with end results from the first test. 2  2  2  Subjects were able to work longer in the second test although there was no significant change in V 0  2m a x  - This seems to suggest that successive exercise bouts do not magnify  EIAH, but the mechanism is present during each exercise test. The role of chronic, recurrent or intense exercise plays on the development of EIAH still remains unanswered. Methods of quantifying E I A H E I A H should be measured directly by measurement of arterial blood gases (Dempsey et al., 1999) and these measurements must be corrected for esophageal temperature. Temperature correction is important because temperature is known to increase -1.5 to 2 °C over a standard exercise test and even more when the exercise protocol has heavy-load endurance exercise (Dempsey et al., 1999). The correction factor is known to be -5% for every 1 °C drop for Pa0 and PaC0 (Dempsey et al., 2  2  1999). Failure to correct for temperature would drastically overestimate ideal alveolar  93 PO2 and A-a VO2 difference. Ear oximetry is acceptable if subjects are not expected to desaturate less than 10% of resting values (Dempsey et al., 1999). Exercise-induced arterial hypoxemia, VO2 max and work performance A significant inverse relationship exists between V 0 a x a n d %Sa02 measured 15 2 m  minutes into constant load treadmill exercise at 95% VO2 max (Williams et al., 1986). Others have demonstrated less of a relationship (Harms et al, 1998). The discrepancy in this relationship may be due to the differences in the populations studied. A key question is whether E I A H can have serious effects on maximal oxygen uptake. This arises from the reduction in arterial O2 content due to limitations of Pa02 (Powers et al, 1993). V02ma is believed to be affected by the transport of O2 across the blood-gas barrier, the X  transport of oxygen to the working muscle is the thought to be the limiting factor in determining VO2 max (Ekblom et al, 1975). If the change of %Sa02 is considered, then the person exhibiting significant reductions of 6 %>Sa02when compared to another subject maintaining %>Hb02to within 2% of resting values, then E I A H is apparent in the first subject during exercise at V02 a and this is said to cause reductions in V02max. m  X  V 0 max can be calculated by using cardiac output and a-v O2 difference, with a difference 2  of % H b 0 o f 4% then there is a reduction of about 4.4% in V 0 2  2 m a x  (Powers et a l , 1989).  In a study by Powers (1989) and colleagues it was demonstrated that exercise-induced reductions in %>Hb02to 92 to 93%> is enough to cause significant effects on V 0 2 x i n m a  elite athletes. There was also an observed l%o decreased in V02maxfor each 1% decrease in %>Hb02 (Pederson, 1992). V02maxhas been shown to decrease by as much as 15%> in the human who desaturates to a maximum of 85-90%> Sa02 (Dempsey et al, 1999).  94 Koskolou and McKenzie (1994) examined arterial hypoxemia and work output during intense exercise in 7 well-trained male cyclists. Three experimental conditions were used to determine the amount of work performed in a 5-minute cycle test (normoxemia (%Sa0 >94%), mild hypoxemia (%Sa0 = 90 ± 1%) and moderate 2  2  (%Sa0 = 87 ± 1%) hypoxemia. Work output was 107.4 KJ, 104.07 KJ, and 102.52 KJ 2  under normoxemia, mild and moderate hypoxemia respectively. Only work differed in the moderate hypoxemia condition compared to normoxemia. Koskolou and McKenzie concluded that maximal cycle performance is significantly impaired when %Sa0 is less 2  than 87% and not under milder saturation levels. It is important to note that there was a clear linear trend between decreasing levels of work with decreasing %Sa0 . Although, 2  this was not statistically significant, this is linear relationship is important in terms of athletic performance. Lawler and associates (1988) postulated that those endurance athletes who demonstrated EIAH at sea level were more likely to suffer gas impairments at altitude when compared to healthy untrained individuals. It can be concluded that elite endurance athletes may possibly exhibit gas exchange limitations during exercise altitude if they demonstrate EIAH at sea level due to limitation of 0 delivery to the working muscle 2  (Martin et al., 1992). The effects of EIAH on V 0  2max  h a v e been demonstrated by  supplying 0 to inspired air during exercise and this has been shown to prevent EIAH 2  (Harms et al., 1998). The results prove that EIAH plays a major role in the reduction of V0  2  ax (Dempsey et al., 1999). It seems that desaturation below 3-4 % is the threshold  m  for consistent negative effects on maximal oxygen uptake (Dempsey et al., 1999). When the subject is given supplemental 0 this delays the onset of the plateau effect of V 0 2  2 m a  x  95 and work rate and allows a higher work rate to be reached (Dempsey et al., 1999). This again illustrates the point that in a healthy trained subject it is the O2 transportation to the working tissue, as determined by blood flow and 0 extraction that is the limiting factor 2  of VC»2max, and not the metabolic capacity of the muscle mitochondria (Wagner et al., 1991). The influence of gender and age on E I A H Exercise-induced arterial hypoxemia in healthy young women In most of the past literature EIAH has been extensively examined in elite male athletes and relatively little research has been looked at in female subjects. The mechanism for EIAH in women may be due to the fact that the adult female lung has a smaller vital capacity, reduced airway diameter, lower resting diffusion capacity for CO and a smaller diffusion surface when comparisons are made to fit male subjects, even when corrected for body size and lower hemoglobin levels (Schwartz et al, 1988). Harms and colleagues (1998) questioned whether healthy young women might be especially susceptible to exercise-induced arterial hypoxemia, even when compared to work rates that were substantially less than in young men. They examined EIAH in twenty-nine healthy young women (VO2 max ranged from 35 to 70 mL-kg" -min" ; VC^max 1  1  57+6 mL-kg" -min" ) by the way of incremental treadmill test to VO2 max during their 1  1  follicular stage of their menstrual cycle. Arterial blood samples were obtained from rest and near the end of each workload. Twenty-two of the 29 subjects, 76% desaturated to 92.3 +/- 0.2%) of resting values. Their results showed that EIAH was more prevalent in those women with higher V02max values, although there were cases of severe hypoxemia at normal V 0 2  m a x  values. EIAH was mainly associated with an excessively widened  96 alveolar to arterial PO2 difference. In 1998, St. Croix et al. investigated the effects of prior exercise on EIAH in 28 healthy young women that were the same subjects in the Harms et al. (1998) study ( V 0 max ranged from 31 to 70 mL-kg" -min" ). At the end of 1  1  2  the first progressive exercise bout only 6 subjects had maintained arterial P 0 near resting 2  levels, the other 22 subjects demonstrated decreases in PaCh of greater than 10 Torr (SaCh, 91.6 ± 2.4%). Subjects were again tested with another progressive exercise test and the authors concluded that EIAH during maximal exercise was lessened and not increased by prior exercise (St. Croix, 1998). The data from these two studies suggests that many active healthy female subjects experience desaturation at a V 0 2  max  e v e n when  VO2 max is substantially less in women athletes compared to that of fit males. The onset of EIAH at submaximal and low VO2 max implies that arterial transport and lung structure are abnormally compromised in these females (Harms et al., 1998). Hopkins et al. (2000) obtained arterial blood gases and cardiac output in 17 active women (VO2 max ranged from 42 to 61 mL-kg" -min" ), there were no significant differences observed in V 0 1  1  2 m a x  between running and cycling. PaCh was lower during running and cycling as was ventilation. The PaCh responses to running and cycling were not significantly different from values in men. Only 4 of the 17 subjects developed EIAH. Wetter et al. (2001) investigated the effects of exhaustive endurance exercise on pulmonary gas exchange and airway function in 16 female athletes (VO2 max ranged from 44 to 56 mL-kg" -min" ; VO2 1  1  max 50±4 mL-kg" -min" ). The authors proposed that perhaps airway inflammation and 1  1  narrowing seen in asthma could contribute to the widened A-aD02 from abnormal ventilation distribution. They concluded that approximately 50% of their subjects developed EIAH. Arterial O2 saturations dropped from 97.6 ± 0 . 5 % at rest to 95.1 ± 1 . 9  % at 1 minute and to 92.5 ± 2.6 % at exhaustion. Plasma histamine increased throughout the test and was inversely related to the fall in P a 0 at the end of exercise. It is 2  interesting to note that 5 of their 16 subjects had PC20 values <16 mg-ml" , which 1  indicates a positive bronchial hyperresponsiveness through a methacholine test. Subjects with hyperreactive airways did not respond to exercise in the same manner as they did to methacholine, this may reflect that even exhaustive exercise does not involve sufficient bronchoprovocation with the release of inflammatory mediators to cause significant changes in peripheral airway diameter. Wetter and colleagues stated that positive bronchial hyperresponsiveness was not directly correlated with exercise-induced changes or exercise-induced arterial hypoxemia. Influence of age on E I A H Prefaut et al. (1994) compared 10 male master endurance cyclists, 10 age matched control subjects, and 10 young high aerobic power male elite cyclists. The results showed that there were significant reductions in P a 0 for all masters cyclists, and for 8 of 2  the 10 young cyclists. None of the control subjects demonstrated any signs of EIAH during the incremental cycling tests. The masters athletes seemed to show greater reductions in P a 0 when compared with younger athletes at all levels of work, perhaps 2  correlating E I A H with increased age in fit individuals (Prefaut et al., 1994). Exercise-induced arterial hypoxemia and histamine release A study by Anselme and colleagues (1994) showed that the drop in arterial partial pressure of 0 (Pa0 ) during maximal exercise was due with an increased in histamine 2  2  release (%H) in elite athletes, whereas there was no change in either Pa0 , or histamine 2  level in the untrained control group. Histamine is known to be an inflammatory mediator  98  that causes increased microvascular permeability to macromolecules and therefore increased transcapillary fluid movement (Mucci et al., 2 0 0 1 ) . This change in pulmonary fluid movement is thought to cause alterations in gas exchange and finally causing EIAH (Mucci et al., 2 0 0 1 ) . More specifically % H is associated with suppression of the ventilation-perfusion distribution. Mucci and associates ( 2 0 0 1 ) studied whether the increase in histamine release associated with EIAH is related to high training-induced changes in basophil and osmolarity factors in arterial blood. Histamine increased during exercise in the highly trained group, but did not increase significantly in the nonhypoxemia or control groups. The results could not show if % H increase is an effect or a cause of EIAH. Conclusion Exercise-induced arterial hypoxemia is thought to result from hypoventilation, ventilation-perfusion inequality and diffusion limitation. While it is generally accepted that the pulmonary system does not limit V C ^ m a x i n healthy subjects, elite athletes seem to be the exception to this rule. Elite athletes exhibit EIAH and these exercise-induced imperfections in the pulmonary system limit VO2 max- Although a number of studies agree that EIAH is clearly demonstrated in this population the explanation for EIAH is unclear (Powers et al., 1 9 9 3 ) . Endurance athletes that demonstrate severe E I A H at sea level show even greater signs of desaturation at altitude. It has now been well established that 4 0 to 5 0 % of highly trained male endurance athletes develop EIAH at near maximal work rates (Powers et al., 1 9 9 3 ) . It seems likely that V A / Q inequality and pulmonary diffusion play a major role in EIAH, although the physiological mechanism of E I A H remains highly debated.  99  Currently no data exists on the prevalence of EIAH and asthma, research is needed to find the incidence rate and whether EIAH is correlated with gender, fitness and severity of asthma. This might give better insight to understand the mechanisms involved with E I A H in healthy subjects and elite athletes.  100  Appendix D. Tables-Individual Data Table 7. Age, height, mass and E V H scores of individual subjects Control (n= 16) CS1 CS2 CS3 CS4 CS5 CS6 CS7 CS8 CS10 CS 11 CS12 CS13 CS14 CS15 CS17 CS18 Mean SD  Age (yrs) 24 23 24 20 25 24 29 30 21 23 36 32 29 27 26 26 26.2 4.2  Height (cm) 152.3 169.5 169.3 161.3 175.9 161.9 177.8 165.2 164.1 159.1 174.1 173.9 167.7 166.4 172.8 164.4 167.2 6.8  Mass (kg) 51.0 54.0 68.1 52.9 62.5 55.9 61.8 54.7 53.4 49.1 52.3 59.6 55.9 65.3 68.3 55.7 57.5 6.0  EVH (%)  Asthma (n =16) SA1 SA2 SA3 SA4 SA5 SA6 SA7 SA8 SA9 SA10 SA11 SA12 SA13 SA15 SA16 SA17 Mean SD  Age (yrs) 24 27 25 27 24 23 24 31 31 40 34 19 24' 21 18 30 26.4 5.7  Height (cm) 168.8 176.3 174.6 167.0 168.7 166.2 165.4 152.8 158.0 154.2 180.2 164.5 159.1 168.6 166.3 160.2 165.7 7.6  Mass (kg) 56.3 55.2 86.9 57.3 54.9 64.9 56.3 47.5 74.1 50.7 83.6 59.1 58.1 60.1 62.7 60.0 61.7 10.9  EVH (%) -43 MCT -10 -19 -11 -13 -11 -14 -10 -34 -16 N/A -18 ECT N/A -14  -5 -4 -6 -8 -9 -9 -6 -7 -5 -4 -9 -8 -3 -6 -9 -4 -6.4 2.1  yrs, years; cm, centimetres; kg, kilograms; %, decrease from resting F E V i values; M C T denotes methacholine challenge test, E C T denotes an exercise challenge test  -17.8 10.3  101  Table 8. Individual subjects hormonal parameters for both testing days Control (n = 16) CS1 CS2 CS3 CS4 CS5 CS6 CS7 CS8 CS10 CS 11 CS12 CS13 CS14 CS15 CS17 CS18 Mean SD  Cycle on Day 1 DP 7 4 4 5 5 8 9 5 8 7 A 9 A 7 5 • 6.4 1.8  Cycle on Day 2 DP 8 7 5 7 7 9 5 7 9 8 A 12 A 8 8 7.7 1.8  Cycle on Day 2 Cycle on Day 1 Asthmatic (n =16) 6 SA1 8 SA2 5 SA3 5 SA4 A SA5 5 SA6 6 SA7 5 SA8 6 SA9 11 SA10 8 SA11 5 SA12 A SA13 5 SA15 * SA16 5 SA17 6.2 Mean 1.8 SD DP, Depoprovera (at the end of a three month cycle); A , amenorrheic  9 10 8 7 A 7 9 6 8 13 9 7 A 9 * 7 8.4 1.8  102 Table 9. Resting lung volumes of individual subjects on Day 1 FEFmax (L/sec) 5.83 5.30 7.25 3.78 4.93 7.85 7.65 7.98 7.07 7.34 5.30 7.53 6.76 4.37 6.03 8.36 6.46 1.40 FEFmax (L/sec) 7.43  FVC (L)  FEV,/FVC  25-75%  2.77 3.75 4.29 3.51 4.16 3.73 4.46 4.22 3.61 2.88 3.98 4.46 3.51 4.39 4.31 4.29 3.90 0.53 FVC (L)  84.11 93.89 78.81 91.82 87.24 86.84 84.68 88.43 92.35 93.56 86.01 90.83 80.65 86.42 69.85 87.24 86.42 6.17 FEV,/FVC  2.55 4.25 2.93 4.56 3.97 3.67 4.00 4.47 4.28 4.03 3.85 4.96 2.59 7.01 2.20 4.36 3.98 1.14 25-75%  3.25  3.66  88.60  3.95  *  *  4.30 2.11 3.55 3.69 3.51 3.11 2.56 2.58 3.95 2.27 3.33 3.61 2.94 3.21 3.20 0.62  5.51 3.74 3.97 4.17 3.90 3.45 3.25 3.32 4.63 3.01 4.04 4.13 3.80 3.84 3.89 0.61  * *  * *  * *  55.45 92.62 88.68 87.18 87.76 74.03 78.58 85.49 75.55 82.85 87.47 77.26 83.66 81.80 9.41  4.49 4.99 4.30 3.90 3.37  1.24 8.73 5.88 6.61 4.09  Control (n= 16) CS1 CS2 CS3 CS4 CS5 CS6 CS7 CS8 CS10 CS 11 CS12 CS13 CS14 CS15 CS17 CS18 Mean SD  FEV,(L)  Asthmatic (n=16) SA1 SA2 SA3 SA4 SA5 SA6 SA7 SA8 SA9 SA10 SA11 SA12 SAO SA15 SA16 SA17 Mean SD  F E V i (L)  2.33 3.52 3.34 3.22 3.63 3.25 3.76 3.73 3.34 2.69 3.42 4.05 2.82 3.72 3.01 3.75 3.35 0.46  *  *  2.23 4.69 1.85 3.52 4.18 2.58 3.32 3.64 0.96  6.99 7.32 5.73 4.74 7.37 5.28 5.81 5.94 1.89  F V C ; 25-75%o, percent of forced expiratory volume occurring between 25 and 75% of the curve; FEFmax, maximal forced expiratory flow in litres per second *Denotes missing data  103  Table 10. Resting lung volumes of individual subjects on Day 2 Control (n = 16) CS1 CS2 CS3 CS4 CS5 CS6 CS7 CS8 CS10 CS 11 CS12 CS13 CS14 CS15 CS17 CS18 Mean SD Asthmatic (n= 16) SA1 SA2 SA3 SA4 SA5 SA6 SA7 SA8 SA9 SA10 SA11 SA12 SA13 SA15 SA16 SA17 Mean SD  FEV, (L)  FVC (L)  FEVi/FVC  25-75%  FEFmax (L-sec ) 5.02 7.59 7.31 5.91 4.48 7.82 8.83 7.46 6.42 6.71 6.37 6.61 6.98 7.92 5.48 8.65 6.85 1  2.43 3.37 3.40 3.21 3.59 3.12 3.89 3.63 3.36 2.71 3.31 3.88 2.83 3.54 2.80 3.68  2.63 3.45 4.31 3.46 3.95 3.63 4.65 4.09 3.56 2.72 3.81 4.23 3.46 4.24 3.94 4.21  92.34 97.63 78.81 51.03 •91.10 85.95 83.64 88.88 94.37 92.11 86.93 92.06 81.68 83.59 71.08 87.49  3.22 5.04 2.98 4.07 6.92 3.31 3.99 4.47 4.50 3.61 3.76 4.89 2.66 3.56 2.13 4.18  3.30  3.77  84.92  3.96  0.43 FEV, (L)  0.55 FVC (L)  11.15 FEV,/FVC  1.12 25-75%  3.21 2.88 4.31 2.56 3.32 3.56 3.47 3.19 2.01 2.49 3.90 2.30 3.42 3.49 2.93 2.91  3.61 3.66 5.30 3.81 3.82 3.98 3.79 3.49 2.62 3.12 4.48 2.77 3.97 4.03 3.84 3.63  88.60 78.32 81.38 67.09 86.88 89.78 91.69 91.94 76.90 82.67 86.91 82.51 86.20 86.51 76.24 80.05  3.95 2.58 4.10 1.79 3.75 4.36 3.90 4.74 1.67 2.20 4.64 2.17 3.69 3.84 2.51 2.30  1.23 FEFmax (L-sec ) 7.43 5.63 8.39 5.74 8.43 6.34 7.11 6.20 4.61 7.00 7.56 5.79 6.01 7.83 5.59 5.30  3.12  3.75  83.35  3.26  6.56  1  1.14 1.05 6.60 0.63 0.60 F E V i , forced expiratory volume; F V C , forced vital capacity; F E V i / F V C , ratio of F E V i to F V C ; 25-75%), percent of forced expiratory volume occurring between 25 and 75% of the curve; FEFmax, maximal forced expiratory flow in litres per second  104  Table 11. Ventilatory parameters at peak exercise of individual subjects on Day 1 Control (n = 16)  V (L-min )  VC0 (L-min )  E  CS1 CS2 CS3 CS4 CS5 CS6 CS7 CS8 CS10 CS 11 CS12 CS13 CS14 CS15 CS17 CS18 Mean SD Asthmatic (n= 16) SA1 SA2 SA3 SA4 SA5 SA6 SA7 SA8 SA9 SA10 SA11 SA12 SA13 SA15 SA16 SA17 Mean SD  V /VC0  2  1  E  V /V0  2  E  RER  2  1  34.5  38.2 40.1 33.3 38.2 32.0 45.7 27.8 34.4 41.8 . 35.4 30.2 31.4 34.5 34.3 27.5 41.5 34.5  1.20 1.20 1.20 1.21 1.23 1.20 1.15 1.23 1.20 1.22 1.10 1.21 1.07 1.19 1.15 1.11 1.2  15.1  15.1  0.1  98.7 101.0 111.8 82.4 101.0 103.8 118.4 106.9 112.0 87.9 107.0 109.0 98.0 107.2 103.0 100.8  3.1 3.3 4.1 2.7 3.8 3.4 4.7 3.8 3.6 3.1 3.4 4.4 3.0 3.6 4.2 2.6  31.8 32.7 36.3 33.1 37.1 32.9 40.3 35.3 32.4 35.2 31.4 40.1 30.5 33.6 40.3 26.2  103.1  3.6  8.9  0.6  V (L-min ) 120.4 109.7 148.6 107.8 110.3 111.7 91.8 89.1 72.4 84.8 113.2 76.3 88.8 112.7 65.0 104.9 E  1  100.5  VC0 (L-min )  V /VC0  2  E  V /V0  2  E  RER  2  1  3.5 3.3 4.4 3.3 3.5 3.5 3.0 2.9 3.3 2.6 3.6 2.8 3.0 4.1 2.8 3.4  34.5 33.7 33.8 32.4 31.2 32.3 30.7 30.7 21.9 32.3 31.7 27.3 29.8 27.5 23.2 30.6  38.7 34.9 44.0 37.737.5 43.3 37.8 37.1 25.8 35.0 47.0 33.3 34.6 33.1 24.4 34.6  3.3  30.2  36.2  1.13 1.07 1.20 1.18 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.16 1.21 1.10 1.15 1.2  0.0 5.9 3.6 0.5 21.0 V , minute ventilation in litres per minute; V C 0 , C 0 production in litres per minute; V E / V C 0 and V E / V 0 , ventilatory equivalents for C 0 and 0 , respectively; RER, respiratory exchange ratio E  2  2  2  2  2  2  105  Table 12. Ventilatory parameters at peak exercise of individual subjects on Day 2 Control  V  VC0  E  (n = 16)  VE/VC0  2  (L-min ) 94.0 CS1 102.0 CS2 108.1 CS3 75.2 CS4 107.7 CS5 116.3 CS6 131.4 CS7 108.6 CS8 107.1 CS10 88.1 CS 11 101.9 CS12 101.5 CS13 97.5 CS14 99.4 CS15 106.9 CS17 87.5 CS18 . Mean 102.1 SD 12.8  (L-min )  Asthmatic (n= 16) SA1 SA2 SA3 SA4 SA5 SA6 SA7 SA8 SA9 SA10 SA11 SA12 SA13 SA15 SA16 SA17 Mean SD  VCOl (L-min )  1  VE (L-min ) 108.6 105.0 134.0 103.3 88.0 100.6 87.0 94.3 70.1 85.6 105.2 78.5 87.4 116.1 73.7 110.7 1  96.7  VE/V0  2  R E R  2  1  30.5 36.4 28.9 31.9 30.2 33.9 29.3 30.2 33.4 31.2 31.1 28.2 33.5 31.0 26.3 34.2  31.8 44.1 34.8 28.4 31.0 41.4 39.0 34.9 41.3 35.8 35.8 36.8 33.9 28.1 28.1 36.3  3.3  31.3  35.1  1.10 1.20 1.20 1.10 1.15 1.20 1.20 1.16 1.20 1.17 1.17 1.30 1.02 1.00 1.11 1.06 1.2  0.6  2.6  4.9  0.1  3.1 2.8 3.7 2.4 3.6 3.4 4.5 3.6 3.2 2.8 3.3 3,6 2.9 3.2 4.1 2.6  '  V /VC0 E  VE7V0  2  R E R  2  1  2.9 3.0 4.2 3.2 2.9 3.1 2.7 2.6 3.4 3.1 3.1 2.7 3.0 4.0 3.1 3.5  37.0 35.5 32.3 31.9 30.1 32.6 32.8 36.0 20.8 28.0 34.4 29.4 29.0 28.9 23.9 31.4  39.2 39.0 36.8 34.9 34.2 37.0 41.2 40.5 21.6 33.4 44.0 33.4 29.9 29.5 24.9 32.9  1.1 1.1 1.15 1.1 1.15 1.15 1.2 1.15 1.1 1.2 1.2 1.15 1.04 1.04 1.05 1.14  3.1  30.9  34.5  1.11  0.1 6.0 4.3 0.4 16.9 V , minute ventilation in litres per minute; V C 0 , C 0 production in litres per minute; V E / V C 0 and V E / V 0 , ventilatory equivalents for C 0 and 0 , respectively; R E R , respiratory exchange ratio E  2  2  2  2  2  2  106  Table 13. Performance at peak exercise of individual subjects on Dayl Control (n = 16) CS1 CS2 CS3 CS4 CS5 CS6 CS7 CS8 CS10 CS 11 CS12 CSB CS14 CS15 CS17 CS18 Mean SD Asthmatic (n=16) SA1 SA2 SA3 SA4 SA5 SA6 SA7 SA8 SA9 SA10 SA11 SA12 SA13 SA15 SA16 SA17 Mean SD XJ-IV, UVU1  V 1 ^V>^  HR (bpm)  V0 (mL-kg'^min") 51.3 no problems 48.0 no problems 49.4 constriction - wheeze 40.7 breathing a bit hard 50.9 no problems/heavy 40.0 no problems 68.8 no problems 56.6 no problems 50.6 heavy legs 50.6 heavy legs 68.0 heavy legs 58.8 heavy legs 50.7 breathing shallow 48.2 breathing shallow 55.1 heavy legs 43.4 heavy legs 51.9  Dyspnea  2 m a x  1  no data 192 198 182 191 191 193 197 202 184 179 194 201 190 179 194 191.1 7.3 HR (bpm)  iii  2  2.6 2.5 3.4 2.2 3.2 2.3 4.3 3.1 2.7 2.5 3.5 3.5 2.8 3.1 3.8 2.4 3.0 0.6  8:2  vo  Dyspnea chest tightness chest tightness wheezy limited breathing no problems constriction constriction dyspnea constriction no problems no problems constriction dyspnea constriction no problems no problems  V0 (L-min ') 3.11 3.14 3.38 2.86 2.94 2.58 2.43 2.4 2.81 2.42 2.41 2.29 2.57 3.41 2.66 3.03 2  2max  (mL-kg'-min ) 57.3 56.8 43.5 51.1 54.4 40.2 43.3 51.0 38.5 47.6 29.3 38.8 45.0 56.8 42.9 52.3 1  193 189 195 199 189 202 208 186 201 177 177 182 184 180 176 178  V0 (L-min" )  188.5  46.8  2.8  10.2  8.0  0.4  ^ s < « / v « b uf  "— » - —}  J  I  "  x  volitional fatigue; V 0 a x , maximal oxygen consumption in liters per minute and millitres per kilogram of body mass per minute 2 m  107  Table 14. Performance at peak exercise of individual subjects on Day 2 Control (n = 16) CS1 CS2 CS3 CS4 CS5 CS6 CS7 CS8 CS10 CS 11 CS12 CS13 CS14 CS15 CS17 CS18 Mean SD Asthma (n=16) SA1 SA2 SA3 SA4 SA5 SA6 SA7 SA8 SA9 SA10 SA11 SA12 SA13 SA15 SA16 SA17 Mean SD  Dyspnea  HR(bpm)  RTE (minutes)  V0 (mL-kg" •min") 58.9 42.5 45.8 50.9 55.9 50.0 55.2 56.5 48.9 50.2 54.7 46.4 51.5 53.7 56.0 43.8 51.3 2 m a x  1  192 ; 196 196 172 194 190 191 189 209 181 183 191 198 183 179 190  heavy legs heaviness constriction no problems heavy legs no problems/heavy no problems max exercise heavy legs heavy legs heavy legs heavy legs limited breathing H+ breathing, VE low heavy legs breathing hard  :  .  6.5 6.8 5.3 5.3 7.3 5.5 9.8 4.3 9.0 4.0 6.3 6.3 9.5 5.8 5.2 7.8 6.5  189.6 8.7 HR (bpm)  Dyspnea  1.8 RTE (minutes)  tightness tightness wheezy constriction dyspnea legs heavy exp flow limitation constriction wheezy constriction body fatigue no tightness tightness hard to breathe constriction no problems wheezy, force exp  8.1 5.5 5.4 5.0 10.3 3.8 3.7 3.5 1.3 3.6 3.5 5.0 4.3 8.8 6.0 5.3 5.2  187.7  V02max  1  3.0 2.3 3.1 2.7 3.5 2.8 3.4 3.1 2.6 2.5 2.9 2.8 2.9 3.5 3.8 2.4 2.9 0.4 V0 (L-min ) 2  (mL-kg"'•min") 49.5 49.0 42.5 51.1 46.8 41.8 37.6 49.4 . 43.9 51.3 29.1 40.4 51.2 65.7 47.8 58.2 47.2  8.4 2.3 11.5 HR, heart rate in beats per minute; Dyspnea, amount of breathlessness felt upon volitional fatigue; V0 ax, maximal oxygen consumption in liters per minute and millitres per kilogram of body mass per minute 2m  2  (L-min )  4.9 1  191 173 209 199 185 198 207 185 199 176 173 181 182 179 181 185  vo  1  2.8 2.7. 3.6 3.0 2.6 2.7 2.1 2.3 3.2 2.6 2.4 2.4 2.9 3.9 3.0 3.4 2.8 0.5  108  Table 15. Individual %Sa0 data measured during progressive exercise Day 1 2  %Sa0 at Control rest (n= 16) 98 CS1 98 CS2 98 CS3 98 CS4 97 CS5 96 CS6 98 CS7 98 CS8 98 CS10 CS 11 . 98 98 CS12 99 CS13 96 CS14 98 CS15 98 CS17 98 CS18 Mean 97.8 SD 0.8 %Sa0 at Asthmatic rest (n= 16) 98 SA1 96 SA2 95 SA3 99 SA4 97 SA5 97 SA6 98 SA7 . 98 SA8 98 SA9 98 SA10 97 SA11 98 SA12 99 SA13 97 SA15 98 SA16 98 SA17 Mean 97.6 SD 1.0 2  2  %Sa0 at 25% 98 98 98 97 96 96 98 96 98 98 98 98 96 98 98 98 2  %Sa0 at 50% 97 97 98 98 97 97 97 97 98 95 98 97 95 98 97 96 2  %Sa0 at 75% 96 97 96 93 96 98 95 97 97 92 97 96 97 96 93 94 2  2  %Sa0 at 100% 93 95 93 91 94 97 90 94 94 89 94 93 95 91 91 95 2  97.4  97.0  95.6  94.7  93.1  0.9 %Sa0 at 25% 98 96 94 99 98 97 97 98 ' 98 98 97 98 99 97 98 98  1.0 %Sa0 at 50% 98 93 92 98 97 97 97 96 97 97 96 98 99 97 98 97 96.7  1.8 %Sa0 at 75% 97 92 90 97 96 97 97 95 95 97 95 98 97 97 96 96  2.0 %Sa0 at 90% 97 91 90 .97 95 97 97 .93 94 96 94 97 96 95 96 96  2  97.5  2  1.8 1.2 %>Sa0, arterial oxyhemoglobin saturation in percent 2  %Sa0 at 90% 95 96 95 91 95 97 92 95 96 92 98 95 97 94 93 94  95.8  95.1  2.1 %Sa0 at 100% 96 91 90 96 93 96 96 92 93 96 92 95 95 93 94 95 93.9  2.1  2.2  2.0  2  2  2  109  Table 16. Individual %Sa0 data measured during progressive exercise Day 2 2  %Sa0 at %Sa0 at %Sa0 at %Sa0 at Control 75% 50% 25% rest (n= 16) 96 97 98 98 CS1 95 98 98 98 CS2 96 97 98 98 CS3 96 98 98 99 CS4 95 97 98 99 CS5 98 99 99 99 CS6 96 97 98 98 CS7 97 98 99 99 CS8 97 97 98 98 CS10 96 96 98 99 CS 11 97 98 99 99 CS12 98 100 99 99 CS13 97 97 98 98 CS14 96 99 98 99 CS15 96 97 98 98 CS17 94 95 95 96 CS18 Mean 96.3 97.5 98.1 98.4 SD 1.1 1.2 0.9 0.8 %Sa0 at %Sa0 at %Sa0 at %Sa0 at Asthmatic 75% 50% 25% (n= 16) rest 97 97 97 98 SA1 91 94 96 97 SA2 97 97 97 98 SA3 97 98 98 98 SA4 97 98 99 99 SA5 97 97 97 97 SA6 98 99 99 99 SA7 94 95 96 96 SA8 95 96 98 97 SA9 97 97 98 98 SA10 95 96 97 97 SA11 97 98 98 98 SA12 96 97 98 98 SA13 96 97 98 98 SA15 96 98 98 98 SA16 96 97 98 98 SA17 Mean 96.0 96.9 97.6 97.8 SD 1.7 0.9 1.2 0.8 %Sa0 , arterial oxyhemoglobin saturation in percent 2  2  2  2  2  2  2  2  2  %Sa0 at 90% 95 94 95 96 94 98 94 96 96 .94 95 96 97 94 93 98 2  %Sa0 at 100% 93 93 94 90 93 97 91 94 94 88 93 93 95 91 88 98 2  95.3  92.8  1.5 %Sa0 at 90% 97 94 97 96 97 96 97 93 94 96 94 97 95 95 95 95  2.8 %Sa0 at 100% 97 93 96 95 95 96 96 91 92 96 92 96 94 94 93 93  2  2  95.5  94.3  1.3  1.8  110  Table 17. Individual pre- post-exercise plasma concentration of sP-selectin Control (n=16)  Mean OD  Pre-exercise (ng-mL' )  MeanOD  1  Postexercise (ng-mL") 82.64 13.05 194.86 293.17 401.04 267.07 195.73 332.31 107.87 309.70 155.72 305.35 412.35 845.57 279.8 201.2  Delta (ng-mL") 1  1  csl cs2 cs3 cs4 cs5 cs7 cs8 csll csl2 csl3 csl4 csl5 csl7 csl8 Mean SD  0.16 0.04 0.10 0.24 0.11 0.24 0.37 0.23 0.14 0.10 0.09 0.15 0.20 0.62 0.2 0.2  140.06 33.93 85.25 207.04 93.95 208.78 325.35 198.34 121.79 87.86 80.03 133.97 174.86 536.75 173.4 128.0  0.10 0.02 0.22 0.34 0.46 0.31 0.23 0.38 0.12 0.36 0.18 0.35 0.47 0.97 0.3 0.2  -57.42 -20.88 109.61 86.12 307.09 58.29 -129.62 133.97 -13.92 221.83 75.68 171.38 237.49 308.83 106.3 73.2  Delta Post(ng-mL ) exercise (ng-mL ) 144.41 285.38 0.33 140.93 0.16 sal -42.63 154.85 0.18 197.47 0.23 sa3 -34.80 98.30 0.11 133.10 0.15 sa4 114.83 186.17 0.21 71.33 0.08 sa7 -65.24 448.88 0.52 514.13 0.59 sa8 220.09 306.22 0.35 86.12 0.01 sa9 -326.22 202.69 0.23 528.92 0.61 salO 153.98 261.85 0.30 107.87 0.12 sail 90.47 133.97 0.15 43.50 0.05 sal2 132.23 302.74 0.35 170.51 0.20 sal3 76.55 135.71 0.16 59.16 0.07 sal6 195.73 480.20 0.55 284.47 0.33 sal7 55.0 249.7 0.3 194.8 0.2 Mean 47.5 246.8 0.3 199.3 0.2 s.d. OD, optical density; ng-mL"', nanograms per millitre; Delta, change in absolute (ng-mL")  Asthmatic (n=16)  Mean OD  Pre-exercise (ng-mL )  Mean OD  1  1  1  Ill Table 18. Individual pre- post-exercise plasma concentration of IL-6 MeanOD  0.57 0.14 0.14 0.11 0.17 0.07 0.07 0.15 0.14 0.06 0.06 0.10 0.37  0.6  0.2  1.3  0.7  0.2 Mean OD  1.1 Delta (pg-mL )  0.06 0.21 0.13 0.08 0.08 0.08 0.13 0.17 0.11 0.16 0.07 0.10  1.2 Postexercise (pg-mL' ) 0.49 1.67 1.04 0.60 0.65 0.60 1.01 1.37 0.84 1.29 0.52 0.79  0.1  0.9  0.4  CS1 CS2 CS3 CS5 CS7 CS8 CS11 CS12 CS13 CS14 CS15 CS17 CS18  0.05 0.05 0.10 0.04 0.05 0.05 0.04 0.05 0.05 0.03 0.05 0.08 0.37  mean  0.1 0.1 Mean OD  Mean OD  SA1 SA3 SA4 SA7 SA8 SA9 SA10 SA11 SA12 SA13 SA16 SA17  0.08 0.09 0.03 0.05 0.02 0.04 0.06 0.08 0.06 0.08 0.04 0.08  0.7 Preexercise (pg-mL") 0.63 0.71 0.27 0.39 0.13 0.33 0.49 0.63 0.49 0.62 0.34 0.66  mean  0.1  0.5  1  1  1  SD Asthmatic (n=16)  Delta (pg-mL )  Postexercise (pg-mL ) 4.53 1.09 1.13 0.88 1.34 0.54 0.54 1.15 1.07 0.50 0.47 0.80 2.90  Preexercise (pg-mL ) 0.37 0.43 0.76 0.32 0.40 0.39 0.29 0.41 0.43 0.24 0.36 0.65 2.90  Control (n = 16)  4.17 0.66 0.37 0.56 0.94 0.16 0.24 0.75 0.64 0.26 0.11 0.142 0  1  1  1  -0.14 0.96 0.77 0.21 0.52 0.27 0.52 0.74 0.34 0.67 0.18 0.13  0.5 0.9 0.1 0.5 0.1 SD OD, optical density; (pg-mL" ), picograms per millitre; Delta, change in absolute (pg-mL" ) 1  Appendix E. Figures Figure 21. E I A standard curves for A. soluble P-selectin, B. IL-6. A.  B.  

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