Egr-1 Regulates Autophagy in Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease

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.

IL13 activates autophagy to regulate secretion in airway epithelial cells

“…In COPD the number of autophagosomes and LC3-II levels are higher in samples of lungs from those with the disease, though the role in goblet cells was not investigated. 45 The same group has shown that cigarette smoke extract or hyperoxia increase autophagy activity in airway epithelial cells and cilia injury. [45][46][47] However, IL13 was not examined in that context.…”

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

“…Intriguingly, increased autophagy in association with apoptosis induction has been demonstrated in COPD pathogenesis. LC3B has been proposed to regulate apoptosis in response to CSE, but a causal link between autophagy status and apoptosis induction remains uncertain (11,(35)(36)(37). In contrast, decreased autophagy in alveolar macrophages derived from smokers has been postulated to be a part of the mechanism for impaired host defense in COPD (38).…”

Autophagy and regulation of cilia function and assembly

“…The lung tissues of COPD patients have been previously shown to accumulate autophagosomes. 102 Lam et al 8 demonstrated that cilia shortening in chronic cigarette smoker correlates with a HDAC6-dependent autophagy degradation of ciliary proteins. In support of the proposed role of autophagy in the negative regulation of ciliary growth, autophagy-impaired cells, Becn1 +/ − , Maplc3b −/− and Hdac6-/Y cells, were protected from cilia shortening.…”