Cigarette smoking induced chronic obstructive pulmonary disease (COPD) is characterized by alveolar epithelial cell death and airway metaplasia and fibrosis. We have shown that the lungs of chronic cigarette smokers without COPD manifest a compensatory response to endoplasmic reticulum stress termed the unfolded protein response (UPR) and that the UPR-related transcription factors, ATF-4 and Nrf2, proteins which regulate anti-oxidant gene expression, are up-regulated by CS in cultured airway epithelial cells. These data raise the possibility that the UPR protects lung cells against oxidant stress and the development of COPD. However, when ER stress is sufficiently severe and protein homeostasis cannot be restored, the UPR causes apoptosis by up-regulating expression of the pro-apoptotic transcription factor, CHOP. These latter observations raise the alternative possibility that the UPR may contribute to the pathogenesis of emphysema by inducing cell apoptosis. Our previous studies were performed in whole lung lysates and cultured airway epithelial cells. We have not studied the in situ response of specific lung cell types to cigarette smoke exposure. Accordingly, the specific Aim of this 2 year project is to characterize the UPR induced by cigarette smoke in a lung cell involved in the pathogenesis of COPD, i.e., airway epithelial cells. We will test the hypotheses that UPR response to cigarette smoke is impaired in the airway epithelial cells of subjects with COPD. Expression of the UPR hallmark proteins (i.e., GRP78, calreticulin, calnexin and protein disulfide isomerase), oxidant defense (i.e., Nrf2 and ATF4) and apoptosis (i.e., CHOP) will be compared in airway epithelial cells from subjects with and without COPD. Cells will be harvested from ex-- smokers without COPD (n=10) and ex-smokers with COPD in GOLD stages II (n=10) and IV (n=10) using the technique of laser capture microscopy applied to HOPE fixed, inflated lung tissue sections. A better understanding of the cellular basis of the UPR induced by CS should enhance our understanding of the pathogenesis of COPD.
Cigarette smoking is a risk factor for chronic obstructive pulmonary disease (COPD), a disease characterized by inflammation, and lung cell death. However, the pathogenesis of this disease remains incompletely understood and current therapies are inadequate. Our recent work shows that a novel biochemical pathway induced in the lung by cigarette smoking can be protective. This response and its biological consequences will be studied in cell type known to be involved with COPD. The results obtained are expected to improve our understanding of cigarette smoke-related lung disease and contribute to the development of new and better treatments.
|Barrero, Carlos A; Perez-Leal, Oscar; Aksoy, Mark et al. (2013) Histone 3.3 participates in a self-sustaining cascade of apoptosis that contributes to the progression of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 188:673-83|