Repeated injury to airways from exposure to irritants (e.g., cigarette smoke) initiates the process of airway remodeling which in some patients, can result in permanent abnormalities in lung function. Chronic airway inflammation and regulation of genes that act down stream of inflammatory mediators play a major role in the pathogenesis of airway remodeling in smokers with chronic obstructive pulmonary disease (COPD). By far the most important risk factor for development of COPD is smoking but a subset of heavy smokers will have a greater decline in lung function than expected and develop severe or end- stage COPD. While inflammatory cells have been found in the lung of smokers with COPD, the nature of """"""""the inflammatory process"""""""" that may be key to understanding the pathogenesis of this disease remains obscure. We have found that activated T lymphocytes persist in the lungs of ex-smokers with end-stage COPD despite years of smoking cessation. Based on the literature and our own data we propose to test the hypothesis that loss of lung function in ex-smokers with end-stage COPD, is mediated through cognate immune mechanisms driven by the T helper 1 (Th1) subset of T lymphocytes. Specifically, a subset of smokers develops an aberrant lung Th1 immune response that orchestrates progressive lung destruction. Furthermore we hypothesize that ex-smokers who develop end-stage COPD can be distinguished from smokers with no or mild COPD by different patters of lung gene activation. To explore these hypotheses, in collaboration with the Houston Veterans Affairs Medical Center (VAMC) lung volume reduction surgery (LVRS) clinical trial, we plan to characterize immunological and genetic phenotypes of 12 non-atopic end-stage COPD, 24 mild COPD with emphysema, and 24 mild or no COPD human ex-smokers. We will determine the immune characteristics of patients with end-stage COPD by addressing the following specific aims:
Aim 1) To determine the dominant immune phenotype of ex- smokers with end-stage COPD.
Aim 2) To determine the mechanism of T cell activation in ex-smokers with end-stage COPD.
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