COPD is characterized by limitation of expiratory airflow that is not reversible. The primary site of theairflow limitation is the small airways. Smoking cessation and/or corticosteroid therapy only partiallyimproves the airflow limitation in COPD. It is not known whether these therapies fail because ofirreversible structural changes or because they have limited effect on the abnormal biologicprocesses in the small airways. This project focuses on the biologic changes in the small airwayepithelium in COPD, and the reversibility of these changes with therapeutic intervention. Wehypothesize that smoking cessation and/or anti-inflammatory therapies do normalize some ofthe altered patterns of gene expression in the small airway epithelium in COPD, and that theidentification of the alterations in small airway epithelial gene expression that are, andarenot, reversed by these interventions will provide targets for the future development oftherapies for COPD. Using newly developed technology with fiberoptic bronchoscopy withbrushings of the small airways to obtain pure small airway epithelium, microarray assessment inCOPD vs normal smokers and non-smokers allowed us to identify genes in different categoriesrelevant to the pathogenesis of COPD. This 'molecular signature' of the small airway epithelium isthe focus of the 3 aims of this proposal.
Aim 1 - to assess the hypothesis that the alterations in geneexpression in the small airway epithelium associated with COPD are at least partially reversible withsmoking cessation. We propose to study healthy smokers and nonsmokers, individuals with COPD(GOLD 0,1,and III), and individuals with early emphysema who do not meet the GOLD criteria.Gene expression will be evaluated at baseline and after smoking cessation.
Aim 2 - To assess thehypothesis that the alterations in gene expression in the small airway epithelium associated withCOPD are at least partially reversible with treatment with corticosteroid.
Aim 3 - To assess thehypothesis that the alterations in gene expression in the small airway epithelium associated withCOPD are at least partially reversible with treatment with an inhibitor of leukotriene synthesis.
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