| Summary: | 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<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<0.03). There was a
significant correlation between Fmax and FEV1 (%predicted) (r=-0.579, p<0.004),
between Fmax and FEV1/FVC (%) (r=-0.720, p<0.003), and between stress and
FEV1/FVC(%) (-0.611, p<0.002). There was no correlation between isotonic
shortening and either measure of pulmonary function. Both force and stress
were significantly increased (p<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<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.]
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