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Chronic Exposure to High Levels of Particulate Air Pollution and Small Airway Remodeling Churg, Andrew; Brauer, Michael; Avila-Casado, Maria del Carmen; Fortoul, Teresa I.; Wright, Joanne L. May 31, 2003

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714 VOLUME 111 | NUMBER 5 | May 2003 • Environmental Health PerspectivesResearch | ArticleConsiderable attention has been devoted to theassociations between levels of ambient particu-late matter (PM) and acute cardiopulmonarymortality, hospital admissions, and exacerba-tions of respiratory and cardiac disease(Dockery 2001; Pope 2000). Less is knownabout chronic effects of high PM exposure,although such exposures have also been associ-ated with increases in cardiopulmonary mor-tality, including increased rates of lung cancer(Beeson et al. 1998; Pope 2000; Pope et al.2002). There is a limited amount of evidenceto suggest that chronic exposure to high levelsof PM may cause chronic airflow obstruction.Abbey et al. (1991, 1995, 1998, 1999) studieda cohort of nearly 4,000 nonsmoking SeventhDay Adventists in California. Significant risksfor the development of new cases of chronicbronchitis and obstructive airways disease wereassociated with increased exposure to ambientPM ≤ 10 µm in diameter and PM < 2.5 µm indiameter (PM10 and PM2.5, respectively)(Abbey et al. 1991, 1995). Increased symptomseverity correlated with PM2.5 and PM10 levels.In more recent analyses with this same cohort,long-term increases in PM10 concentrationswere also associated with lung function decre-ments (Abbey et al. 1998) and increases inmortality from nonmalignant lung disease(Abbey et al. 1999).Studies of women in developing countriesexposed to very high levels of PM emittedfrom cooking with biomass fuels also suggestthat chronic exposures are associated with thedevelopment of chronic airflow obstruction.A case–control study of Mexican womenreported an increased risk of chronic bronchi-tis and chronic airflow obstruction associatedwith cooking with wood (Perez-Padilla et al.1996). The risk of chronic bronchitis was lin-early associated with hour-years of cookingwith biomass fuels. A case–control study con-ducted in Colombia identified a similar riskin women who cooked with biomass fuels(Dennis et al. 1996). Because smoke-induced pathologic abnor-malities in the small airways are one of thecauses of chronic airflow obstruction in ciga-rette smokers, the observation of chronic air-flow abnormalities in individuals with chronichigh PM exposures suggests that PM exposuremight also produce morphologic changes inthe small airways. We have previously reported(Brauer et al. 2001) on the bulk lung particlecontent in a series of women from MexicoCity, a region of chronically high PM (3-yearmean PM10 = 66 µg/m3) and compared themwith lungs of subjects from Vancouver, BritishColumbia, Canada, a city with low PM(1984–1993 average = 25 µg PM10 and 15 µgPM2.5) (Brook and Dann 1997). In that studywe observed that the lungs of the Mexico Citysubjects contained significantly greater particleloads, including numerous aggregates of ultra-fine particles that appeared to be ambient com-bustion products. Because these women werenever-smokers, had not cooked with biomassfuels, and had no known occupational particleexposures, their lungs are suitable for examin-ing the morphologic effects of chronic expo-sure to high PM. In this article we examine thesmall airways.Materials and Methods Subject. The studies described in this articlewere approved by the University of BritishColumbia institutional review board.Portions of 50 autopsy lungs from womenwho were lifelong residents of Mexico Citywere obtained from the autopsy service of acardiovascular referral hospital. None of thewomen had died of respiratory disease. Onlywomen were selected for the Mexico Citygroup to decrease the possibility of occupa-tional particle exposures.For this study, we randomly selected 20 ofthe 50 cases as a test group, and for compari-son, we obtained 20 autopsy lungs from ageneral hospital autopsy service in Vancouver.Because of the random selection from the samepool of 50 autopsy lungs, 8 of the Mexico Citysubjects in the current study were the same asthose previously analyzed in our article on PMretention in human lungs (Brauer et al. 2001),although in that report we dissected parenchy-mal tissue, whereas here we focus on airwaytissue. In both Mexico City and Vancouver,occupational, smoking, and residential histo-ries were obtained from interviews with rela-tives, using a standardized questionnaire. ForVancouver, lungs from both men and women(7 men, 13 women) were used because of lowautopsy rates and difficulties in obtaining inter-views with relatives. Subjects with any form ofchronic lung disease were excluded from thestudy. All subjects in the study were never-smokers, had not worked in dusty occupations,had not cooked with biomass fuels, and werelifelong residents of Mexico City or residents ofVancouver for > 20 years prior to death.Chronic Exposure to High Levels of Particulate Air Pollution and SmallAirway RemodelingAndrew Churg,1 Michael Brauer,2 Maria del Carmen Avila-Casado,3 Teresa I. Fortoul,4 and Joanne L. Wright11Department of Pathology and 2School of Occupational and Environmental Hygiene, University of British Columbia, Vancouver, BritishColumbia, Canada; 3Instituto Nacional de Cardiologia Ignacio Chavez, Mexico City, Mexico; 4Department of Cellular and TissularBiology, Universidad Autonoma de Mexico, Mexico City, MexicoAddress correspondence to A. Churg, Department ofPathology, University of British Columbia, 2211Wesbrook Mall, Vancouver, BC, Canada V6T 2B5.Telephone: (604) 822-7775. Fax: (604) 822-7635.E-mail: achurg@interchange.ubc.caThis work was supported by grant MOP 42539from the Canadian Institutes of Health Research anda grant from the BC Lung Association.The authors declare they have no conflict of interest.Received 8 October 2002; accepted 19 December2002.Recent evidence suggests that chronic exposure to high levels of ambient particulate matter (PM)is associated with decreased pulmonary function and the development of chronic airflow obstruc-tion. To investigate the possible role of PM-induced abnormalities in the small airways in thesefunctional changes, we examined histologic sections from the lungs of 20 women from MexicoCity, a high PM locale. All subjects were lifelong residents of Mexico City, were never-smokers,never had occupational dust exposure, and never used biomass fuel for cooking. Twenty never-smoking, non–dust-exposed subjects from Vancouver, British Columbia, Canada, a low PMregion, were used as a control. By light microscopy, abnormal small airways with fibrotic wallsand excess muscle, many containing visible dust, were present in the Mexico City lungs. Formalgrading analysis confirmed the presence of significantly greater amounts of fibrous tissue and mus-cle in the walls of the airways in the Mexico City compared with the Vancouver lungs. Electronmicroscopic particle burden measurements on four cases from Mexico City showed that carbona-ceous aggregates of ultrafine particles, aggregates likely to be combustion products, were presentin the airway mucosa. We conclude that PM penetrates into and is retained in the walls of smallairways, and that, even in nonsmokers, long-term exposure to high levels of ambient particulatepollutants is associated with small airway remodeling. This process may produce chronic airflowobstruction. Key words: air pollution, chronic obstructive pulmonary disease, COPD, small air-ways disease. Environ Health Perspect 111:714–718 (2003). doi:10.1289/ehp.6042 available viahttp://dx.doi.org/ [Online 19 December 2002]The age at death (mean ± SD) was 66 ± 9years for the subjects from Mexico City. Mostof the subjects from Mexico City were home-makers. None had a history of asthma or anyother chronic lung disease. The causes of deathwere mostly cardiac failure or complications ofmyocardial infarction. The mean age at deathin the patients from Vancouver was 76 ± 11years. None had a history of chronic lung dis-ease; some had minor degrees of terminal acutepneumonia. There was a wide variety of causesof death, including complications of Alzheimerdisease, myeloma, peritoneal mesothelioma in apatient who had received abdominal radiationfor a seminoma, renal failure, cerebrovascularaccidents, peritonitis, and bowel infarctions.Histologic preparations. The Mexico Citylung tissue generally consisted of an approxi-mately 6-cm cube of fairly central lung con-taining both parenchyma and large airways.Two 2 × 1 cm histologic sections were pre-pared from this tissue for each case. As com-parable an area of lung as possible wasselected for the lungs from Vancouver, andtwo histologic sections were again prepared.For grading, the sections were stained withMovat’s Pentachrome stain. Because the lungswere not inflated in a standard fashion, weused a visual grading scheme (Wright et al.1985) to evaluate airway wall fibrosis and air-way wall muscle in the membranous bronchi-oles (MBs) and respiratory bronchioles (RBs).Using this scheme, the airways from the testslides were compared with a set of standardphotographs and graded from 0 to 3, with agrade of 3 indicating severe abnormality. Forthe Mexico City lungs, 121 RBs and 126s MBwere graded; for the Vancouver lungs, 96s RBand 81 MBs were graded. The grading wasdone in a blinded fashion. MBs and RBs weregraded separately; the grades for all airwayswere then summed and expressed as a propor-tion of a possible maximum score for eachcase. Statistical analysis was conducted usingthe grade (fibrosis or muscle, type of airway)for each case. Because these were autopsylungs, inflammation may reflect any numberof causes, and we did not grade numbers ofinflammatory cells. Particle burden measurements. In orderto determine whether PM particles penetrateinto the airway walls, we randomly selectedfour lungs from the 50 Mexico City autopsysamples available to us for airway particle bur-den analysis. Again, because of random selec-tion, two of the lungs analyzed in this studyfor airway particle content had been previ-ously analyzed and reported in our study onparenchymal particle retention in MexicoCity lungs (Brauer et al. 2001). For each case,airway mucosa, defined as all tissues betweenthe cartilage and the lumen, was microdis-sected from mainstem, segmental, and sub-segmental bronchi, as well as carinas of theseairways, and in some cases from MBs. Detailsof the dissection procedure have been pub-lished elsewhere (Churg et al. 1999). The tis-sues were then dissolved in bleach and theparticles were collected and examined in ananalytical electron microscope as previouslydescribed (Churg et al. 1999). Particles wereidentified by morphology and chemical com-position, and concentrations were expressedas particles per gram dry tissue.Article | Air pollution and airway remodelingEnvironmental Health Perspectives • VOLUME 111 | NUMBER 5 | May 2003 715Figure 1. MBs in representative images of a lung from Vancouver (A,B) and representative images of alung from Mexico City (C,D). Note the greatly thickened airway wall and the marked increase in fibrous tis-sue and muscle in the airway walls in the Mexico City lung (C,D). Magnification: ×50 for (A) and (C); ×200for (B) and (D).Figure 2. RBs in representative images of lungs from Vancouver and Mexico City. (A) Lung from Vancouver;the airway wall is very thin with almost no muscle present. (B) Lung from Mexico City; there is marked thick-ening and distortion of the airway wall along with dust deposition. (C,D) RBs from another lung from MexicoCity showing extensive dust deposition in the wall. Magnification: ×50 for (A–C); ×200 for (D).Statistics. Amounts of fibrous tissue andmuscle were compared between specimensfrom Mexico City and Vancouver, and alsobetween men and women in the Vancouvercases, by one-way analysis of variance usingSYSTAT (Systat Inc., Evanston, IL, USA). ResultsOn histologic inspection, both the MBs andRBs in the lungs from Mexico City wereabnormal, with variably increased amounts ofmuscle and fibrous tissue compared with thelungs from Vancouver (Figures 1 and 2). TheMBs in the Mexico City lungs generallyshowed no increases or only minimal increasesin pigmented dust in the walls, but many ofthe RBs contained considerable amounts ofpigmented dust (Figure 2C,D). No dust oronly very small amounts were seen in the RBsof Vancouver lungs (Figure 2A). Many of theairways from Mexico City also showed lumenaldistortion (Figure 1C).Because the men from Vancouver might,despite the screening process, have had moredusty occupations or be otherwise differentfrom women, a statistical comparison of thehistologic grades between the Vancouver menand women was carried out. No statisticaldifferences were found, and thus all 20Vancouver cases were used for comparisonwith the Mexico City cases.Table 1 shows the mean grades of all casesper location for muscle and fibrous tissue byairway type. Significantly greater amounts ofboth components were seen in the MexicoCity lungs for both MBs and RBs. The differ-ences are presented graphically as box plotsshowing the value for each case in Figure 3. The electron microscopic analysis revealedthe presence of chained carbonaceous or car-bon/sulfur aggregates of spherical ultrafineparticles in the airway mucosa in all four casesfrom Mexico City. We have previously shown(Brauer et al. 2001) that these particle aggre-gates are similar to particle aggregates sampledfrom ambient air in Mexico City. Particles ofthis type were found in 20 of the 25 airwaysamples examined and in all locations includ-ing the mainstem bronchi, segmental andsubsegmental bronchi, and the MBs; concen-trations of particles ranged from 10 to> 1,000 × 106/g dry tissue (Figure 4). Thegeometric mean size of the individual parti-cles making up the aggregates varied from0.040 to 0.067 µm, and of the aggregatesthemselves from 0.34 to 0.54 µm (Table 2).These are similar in size to the carbonaceousaggregates found in the parenchyma in theMexico City lungs in our previous study(Brauer et al. 2001).DiscussionAlthough there is epidemiologic evidenceindicating that chronic exposure to PM isassociated with chronic airflow obstruction,the anatomic basis of this effect is unknown.The traditional view of the effects of ambientPM on lung structure can be found in stan-dard texts such as Spencer’s Pathology of theLung (Spencer 1985), which states thatanthracosis (i.e., black particles inhaled fromthe air and retained in the lung) is not associ-ated with lung pathology. However, morerecent studies suggest that, in fact, ambientPM does produce airway disease. Souza et al.(1998) evaluated forensic (violent death)autopsy lungs from 34 residents of low PMregions of Brazil and 50 residents of SãoPaolo, a high PM region (mean annual PM10approximately 80–100 µg/m3 between 1991and 1995). Histories were obtained from rela-tives. About 90% of subjects were male. Theoverall mean age at death was approximately28 years, and 61% were smokers (averagepack-years about 7). Small airways weregraded visually for four parameters (anthra-cosis, inflammation, wall thickness, andmucus hypersecretion); in addition, thegland/wall ratio in the large airways wasdetermined. No differences were seenbetween high-PM and low-PM subjects ingland/wall ratio, regardless of smoking status.The other four measures were generally largerArticle | Churg et al.716 VOLUME 111 | NUMBER 5 | May 2003 • Environmental Health PerspectivesTable 1. Grading of changes in small airways (mean ± SD of grade for all cases per location).Mexico City Vancouver SignificanceRBsMural fibrosis grade 38 ± 17 7 ± 6 p < 0.001Mural muscle grade 45 ± 20 6 ± 8 p < 0.001MBsMural fibrosis grade 58 ± 9 23 ± 11 p < 0.01Mural muscle grade 69 ± 18 33 ± 18 p < 0.01A BC D9080706050403020100Vancouver Mexico City Vancouver Mexico City2001000Vancouver Mexico City Vancouver Mexico City1009080706050403020100706050403020100Percent maximumpossible scorePercent maximumpossible scoreFigure 3. Box plots of airway fibrosis and muscle grades by case. (A) MBs, fibrosis grades. (B) MBs, musclegrades. (C) RBs, fibrosis grades. (D) RBs, muscle grades.The box shows the 25th and 75th percentiles, thehorizontal line is the median value, and the whiskers show the 5th and 95th percentiles. For each measure,the Mexico City lungs show significantly greater abnormalities than the Vancouver lungs.2,0001,6001,2008004000MainstemSample siteSegmental Carinas MBMillions of particles/g dry tissueFigure 4. Plot showing the concentrations of car-bonaceous aggregates in the mainstem bronchi,segmental/subsegmental (labeled “segmental”)bronchi, large airway carinas, and MBs over all thesamples examined.Table 2. Sizes of carbonaceous aggregates (µm).aSize of individual Size of Case particles in aggregates aggregates1 0.067 (2.35) 0.54 (1.73)2 0.040 (1.60) 0.34 (1.74)3 0.051 (2.04) 0.53 (1.62)4 0.048 (1.98) 0.50 (1.70)aValues are geometric mean (geometric SD)..in smokers and somewhat larger comparinghigh-PM to low-PM subjects in either thesmoking or nonsmoking groups. There was aclear correlation between anthracosis score,used as a surrogate of PM exposure, and eitherairway wall inflammation or airway wall thick-ness. The findings of Souza et al. (1998) wouldsuggest that long-term residence in high PMregions leads to chronic structural changes inthe airways, changes that, in cigarette smokers,have been shown to correlate with clinical air-flow obstruction (Wright et al. 1992).However, in that study more than half thesubjects were smokers and more than half hadoccupational dust exposures. Although the sta-tistical analysis still indicated an effect of PMlevels after adjustment for smoking and occu-pational dust exposure, the authors’ graphicalrepresentations of their data suggest that thePM effects, apart from anthracosis, were small.Pinkerton et al. (2000) examined theautopsy lungs of 42 Hispanic males from theFresno County Coroner’s Office; this regionof California has high PM (during the timethe samples were collected, mean PM10 levelsin Fresno were 43.5 µg/m3 and mean PM2.5levels were 22 µg/m3). The median age of thesubjects was 33 years, and approximately halfwere smokers. Most had worked in local farm-ing operations or in blue-collar occupations.Lungs were inflated with fixative and carefullymicrodissected along two paths into the leftupper lobe. Histologic samples were takenfrom airway generations 2, 4, 6, 9, and distalparenchyma containing terminal bronchiolesand RBs.Pinkerton et al. (2000) found histologicevidence of cigarette smoke injury (chronicbronchitis and small airways disease) in abouthalf the subjects. Few abnormalities werenoted in the larger airways, but the small air-ways showed both carbonaceous dust andbirefringent particles in most cases. Particleloads were highest in the walls of generation 1RBs and in MBs. The most intriguing obser-vation was that the amount of dust (pigment)correlated with the degree of fibrosis in theseairways. The study of Pinkerton et al. (2000)was very carefully designed and undertakenand was intended to show that exposure toPM caused abnormalities in the small airways,but the inclusion of a high percentage of sub-jects who were smokers or had occupationaldust exposure (farming is known to be a verydusty process in this region) may confoundthe results. Smoking produces lesions similarin location and appearance [pigmentation,inflammation, and fibrosis of the walls of themembranous and to a certain extent the RB(Wright et al. 1992)] to those caused bydusts, although smoke-induced lesions tendto be more proximal in the bronchioles anddust-induced lesions more distal. Synergisticinteractions between smoke and dust mayamplify dust effects as indicated in animalmodels (Tron et al. 1987); thus, determiningwhat effects really are chronic ambient PMeffects is not straightforward. In this study we have attempted to over-come these limitations by selecting a group ofsubjects who were never-smokers, did not havea history of occupational dust exposure, and,for the women from Mexico City, did notcook with biomass fuels. Cooking with bio-mass fuels produces very high PM exposures(Brauer et al. 1996; Smith 1993), has beenassociated with chronic airways disease (Denniset al. 1996; Perez-Padilla et al. 1996), and caneven produce a form of pneumoconiosis whencooking occurs in enclosed spaces.It is possible that other confounders suchas differences in exposure to environmentaltobacco smoke might exist between theVancouver and Mexico City subjects. Giventhat airway abnormalities in cigarette smokersare, in a broad sense, proportional to theamount of smoking, it is extremely unlikelythat such exposures could produce the typesof airway lesions that were observed.Nevertheless, the available data did not allowus to accurately characterize environmentaltobacco smoke exposure or other potentialconfounders such as genetic differences, andthis must be recognized as a limitation of theavailable data.Because of difficulties in obtaining autop-sies and interviews for our Vancouver controlgroup, we were forced to use both men andwomen and to use a population that was, onaverage, 10 years older than the test group.Although this may be considered a limitationof our analysis, it is most likely that this agedifference would decrease the ability to detectdifferences between the Mexico City andVancouver groups, as dust and airway abnor-malities tend to accumulate with age. Anadditional issue is that the autopsy lungs fromthe two sites were not saved in their entirety,and we could not exactly match sample sites.However, given the marked differencesbetween the Mexico City and Vancouverlungs, it is unlikely that sampling variations,variations that are effectively random, couldexplained the differences observed.PM is not the only air pollutant present inhigher concentrations in Mexico City com-pared with Vancouver. The concentrations ofozone, nitrogen dioxide, sulfur dioxide, andcarbon monoxide are also considerably higher(Brauer M. Unpublished data). Thus, onecould argue that our findings might relate to apollutant other than PM. However, becauseessentially identical types of airway lesions arefound in workers occupationally exposed tomineral dusts in the absence of other pollu-tants (Wright et al. 1992), we believe that PMis the primary pollutant responsible for theseeffects. It is possible that synergisms betweenPM and other pollutants might play a role inaugmenting these lesions, particularly sinceexperimental data suggest that combinationsof particles plus ozone lead to greater particleuptake by epithelial cells and greater inflam-matory responses compared with particlesalone (Adamson et al. 1999; Churg et al.1996). It is also possible the other pollutantsthat adhere to particles may play a role in theobserved differences in airway lesions.The present results suggest, therefore, thatchronic exposure to high levels of PM pro-duces distinctly visible small airway lesions, inparticular, increases in fibrous tissue, muscle,and, in the RBs, pigmented dust. The mor-phologic changes seen in the lungs fromMexico City are very similar to those found incigarette smokers and in workers with high-level occupational exposure to many kinds ofdusts (Wright et al. 1992), and in both ofthese groups, airway remodeling of this typeappears to be associated with chronic airflowobstruction. Our findings thus provide ananatomic basis for the functional abnormali-ties detected in persons with chronic exposuresto elevated PM concentrations.In our previous analysis of bulk lung sam-ples from our Mexico City test population, wefound numerous chain aggregates of ultrafinecarbon or carbon plus sulfur particles (Braueret al. 2001); the same particles were found inMexico City air and are very similar in termsof morphology, size, and composition to pub-lished descriptions of diesel exhaust particles(Harrison et al. 1999). We have now shownthat exactly the same particles are present inthe airway walls. Because the current approachis a bulk analysis of airway tissue, we cannotdetermine exactly where in the airway wallsthese particles reside, but the light microscopicimages of black pigment in the walls of the air-ways, particularly the RBs, suggest that theyare in the connective tissue beneath the base-ment membrane, rather than in the epithe-lium. Thus, these electron microscopic dataconfirm for the first time that this visible pig-ment is PM that has entered and beenretained in airway walls. Tissue penetration appears to require highlocal PM levels, as we have never observedthese particles in extensive electron micro-scopic examinations of the airways of lungsamples from Vancouver residents (Churg etal. 1999). Our intention here was only todemonstrate that PM particles enter and areretained in the airway walls, and hence we didnot sample a larger number of lungs nor pur-sue in detail the question of particle concen-tration by airway location and size.Depending on particle type, entry of parti-cles into the airway wall may be associatedwith a subsequent fibrogenic response. Wehave previously shown in a tracheal explantArticle | Air pollution and airway remodelingEnvironmental Health Perspectives • VOLUME 111 | NUMBER 5 | May 2003 717Article | Churg et al.718 VOLUME 111 | NUMBER 5 | May 2003 • Environmental Health Perspectivessystem using a model air pollution particlethat this is a direct effect of the particle anddoes not require added inflammatory cells(Dai et al. 2002). We suggest, therefore, thatPM particles are fibrogenic in individualsexposed to high levels for long periods, andthat the resulting airway wall remodeling maybe associated with chronic airflow obstruction.REFERENCESAbbey DE, Burchette RJ, Knutsen SF, McDonnell WF, LebowitzMD, Enright PL. 1998. Long-term particulate and other airpollutants and lung function in nonsmokers. Am J RespirCrit Care Med 158:289–298.Abbey DE, Mills PK, Petersen FF, Beeson WL. 1991. Long-termambient concentrations of total suspended particulates andoxidants as related to incidence of chronic disease inCalifornia Seventh-Day Adventists. Environ Health Perspect94:43–50.Abbey DE, Nishino N, McDonnell WF, Burchette RJ, Knutsen SF,Lawrence Beeson W, et al. 1999. Long-term inhalable parti-cles and other air pollutants related to mortality in non-smokers. Am J Respir Crit Care Med 159:373–382.Abbey DE, Ostro BE, Petersen F, Burchette RJ. 1995. 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