Structure and function of human peripheral airways in obstructive airways disease
Creators: name: Opazo Saez, Anabelle Marjorie
Publisher: name: University of British Columbia
Year: 2009

description: 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&lt;70%) patients (62±10 yrs, mean±SD). Thickening of the smooth muscle, and not the inner or outer wall area, was significantly related to pulmonary function parameters, FEV1 (forced expiratory volume in 1s of the forced vital capacity), FEV1/FVC (ratio of FEV1 to the forced vital capacity), FEF25-75 (forced expiratory flow at 50% of FVC), DFEV1 (change in FEV1 after bronchodilator administration) (p&lt;0.03). There was a significant correlation between Fmax and FEV1 (%predicted) (r=-0.579, p&lt;0.004), between Fmax and FEV1/FVC (%) (r=-0.720, p&lt;0.003), and between stress and FEV1/FVC(%) (-0.611, p&lt;0.002). There was no correlation between isotonic shortening and either measure of pulmonary function. Both force and stress were significantly increased (p&lt;0.05) in OB (Fmax=0.87±0.80 g, stress=76±47 mN/mm²) versus NOB (Fmax=0.42±0.18 g, stress=51± 21 mN/mm²). ASM and ASM/Dmax were both significantly increased in the OB patient group (p&lt;0.05). In addition, OB ASM exhibited decreased relaxation responses to MK886, a leukotriene biosynthesis inhibitor, and significant reduction in the force and shortening contractions when compared to NOB. These changes in contractility were not accompanied by alterations in the content of contractile and noncontractile proteins, or in the content or composition of connective tissue surrounding the muscle. These results suggest that obstructive airways disease is associated with an increase in the ability of the ASM to generate force. [Scientific formulae used in this abstract could not be reproduced.]