Abstract
BackgroundChronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear.Methodology and Principal FindingsIncreased autophagy was observed in lung tissue from COPD patients, as indicated by electron microscopic analysis, as well as by increased activation of autophagic proteins (microtubule-associated protein-1 light chain-3B, LC3B, Atg4, Atg5/12, Atg7). Cigarette smoke extract (CSE) is an established model for studying the effects of cigarette smoke exposure in vitro. In human pulmonary epithelial cells, exposure to CSE or histone deacetylase (HDAC) inhibitor rapidly induced autophagy. CSE decreased HDAC activity, resulting in increased binding of early growth response-1 (Egr-1) and E2F factors to the autophagy gene LC3B promoter, and increased LC3B expression. Knockdown of E2F-4 or Egr-1 inhibited CSE-induced LC3B expression. Knockdown of Egr-1 also inhibited the expression of Atg4B, a critical factor for LC3B conversion. Inhibition of autophagy by LC3B-knockdown protected epithelial cells from CSE-induced apoptosis. Egr-1 −/− mice, which displayed basal airspace enlargement, resisted cigarette-smoke induced autophagy, apoptosis, and emphysema.ConclusionsWe demonstrate a critical role for Egr-1 in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo. The induction of autophagy at early stages of COPD progression suggests novel therapeutic targets for the treatment of cigarette smoke induced lung injury.
Highlights
Chronic obstructive pulmonary disease (COPD) is defined as a preventable and treatable disease state characterized by airflow limitation that is not fully reversible
We demonstrate a critical role for early growth response-1 (Egr-1) in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo
Increased autophagy in human COPD lung tissues To investigate the role of autophagy in the pathogenesis of COPD, lung tissue sections from control or COPD patients were analyzed for the expression of autophagy proteins
Summary
Chronic obstructive pulmonary disease (COPD) is defined as a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. Cigarette smoking is the most important risk factor for the development of COPD [2]. The cellular and molecular mechanisms for COPD pathogenesis remain incompletely understood [4]. Gene expression profiling studies of human clinical COPD lung tissue have suggested candidate molecular targets for disease progression and therapeutic intervention [5,6]. We identified the early growth response-1 (Egr-1) as a gene whose expression changed significantly in COPD [6]. The role of Egr-1 in the pathogenesis of COPD remains incompletely understood. Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear
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