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Structure and function of human peripheral airways in obstructive airways disease Opazo Saez, Anabelle Marjorie

Abstract

Obstructive airways diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma are characterized by airflow obstruction, and by structural changes in the airway wall associated with chronic inflammation. The degree to which these changes are related to airflow obstruction and hyperresponsiveness is not completely understood. The aims of the investigations carried out in this thesis were to relate peripheral airway dimensions, in vitro contractile properties, and muscle protein content, to pulmonary function measured before surgery in subjects who had varying degrees of airflow obstruction. The hypothesis was that an increase in airway smooth muscle (ASM) mass and contractility leads to exaggerated airway narrowing and airflow obstruction, and that the increased ASM is accompanied by dedifferentiation of the muscle during airway remodelling. Connective tissue deposition could also take place in the airway wall and lead to increased passive elastance and attenuation of bronchoconstriction. Airway dimensions of isolated human peripheral airways were measured by morphometry and the passive and active mechanical properties were measured in vitro by myography. The maximal isometric force (Fmax), stress (Fmax/ASM), airway diameter at Lmax (Dmax), maximal isotonic shortening (%Lmax), normalized airway smooth muscle (ASM/Dmax) were determined. Western blot analysis was performed to characterize the content and distribution of myosin and actin. The smooth muscle phenotype was assessed by the ratio of muscle (SM-MHC) to non-muscle (NM-MHC) myosin, and of α-actin to total actin. Pulmonary function was assessed prior to surgery. Fifteen airways were studied from nonobstructed (NOB), and 15 from obstructed (OB, FEV1/FVC

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