Amir_Soltani_whole _thesis.pdf (4.07 MB)
Airway remodelling in smokers with or without chronic obstructive pulmonary disease (COPD) and the effects of inhaled corticosteroids on remodelling in COPD
thesisposted on 2023-05-26, 06:31 authored by Soltani Abhari, A
`Introduction:` Smoking-related COPD is a worldwide health problem. Airway remodelling is defined as structural changes occurring in chronic inflammatory diseases of the airways. Our knowledge about airway remodelling in COPD is very limited. My preliminary observational study of bronchial biopsies (BB) from COPD subjects revealed reticular basement membrane (Rbm) fragmentation and vascular changes. I hypothesised that these changes are specific for COPD and are related to the angiogenic activity of vascular endothelial growth factor (VEGF) and transforming growth factor-‚àövº (TGF-‚àövº). I also aimed to study the effects of inhaled corticosteroids (ICS) on these airway changes. `Methods:` A cross-sectional study compared BB from current smokers with COPD (SCOPD), ex-smokers with COPD (ES-COPD), current smokers with normal lung function (S-N) and healthy nonsmoking (H-N) subjects. BB were stained with anti-Collagen IV, anti-VEGF and anti-TGF- ‚àövº antibodies. Rbm fragmentation and vessels in the Rbm and lamina propria (LP) were measured. Anti-Factor VIII antibody was compared with anti-Collagen IV antibody in detecting vessels. Then a double-blind, randomized and placebo controlled study assessed the effects of ICS on airway remodeling, VEGF and TGF- ‚àövº in COPD. \\(Results:\\) Airway remodelling changes were also detectable in S-N. The Rbm was fragmented. The length of splits was significantly greater in both COPD groups and in S-N than controls (p<0.02). The Rbm was hypervascular and the LP hypovascular in current smokers compared with controls (p<0.05). Vessels stained for VEGF and TGF-‚àövº were increased in the Rbm of both COPD groups and S-N (p<0.05). Factor VIII antibody confirmed my finding of hypovascularity of the LP in S-COPD. ICS reversed Rbm splitting but did not have any effect on vessel remodelling and angiogenic activities. `Discussion:` My studies revealed novel aspects of Rbm and vascular remodelling in BB from COPD subjects and S-N and for the first time showed that ICS are effective on Rbm changes in COPD. Rbm fragmentation, we think, is probably a consequence of the effects of proteolytic enzymes on the Rbm due to activation of epithelial-mesenchymal transition (EMT) by smoking. This is under more investigation in our group. My study could not explain the mechanisms to vessel changes in current smokers. Further studies to examine the role of other angiogenic/antiangiogenic factors are now needed. Absence of vascular changes in ES-COPD subjects may imply that vascular remodelling is reversible with smoking cessation, but to test this we need a longitudinal smoking cessation study.
Rights statementCopyright Copyright 2010 the author. A paper related to chapter five has been published as: Soltani, A., Reid, D. W., Sohal, S. W., Wood-Baker, R., Weston, S., Muller, H. K., Walters, E. H., 2010, Basement membrane and vascular remodelling in smokers and chronic obstructive pulmonary disease: a cross-sectional study, Respiratory research, 11: 105. It was published using a Creative Commons Attribution 2.0 Generic (CCBY 2.0) license (https://creativecommons.org/licenses/by/2.0/)