Dataset Information

Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease.

ABSTRACT:

Background

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.

Methodology and principal findings

Increased 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.

Conclusions

We 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.

SUBMITTER: Chen ZH

PROVIDER: S-EPMC2552992 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsRecent studies have shown that cigarette smoke (CS)-induced oxidative stress impairs autophagy, resulting in aggresome-formation that correlates with severity of chronic obstructive pulmonary disease (COPD)-emphysema, although the specific step in autophagy pathway that is impaired is unknown. Hence, in this study, we aimed to evaluate the role of master autophagy transcription factor EB (TFEB) in CS-induced COPD-emphysema pathogenesis.ResultsWe first observed that TFEB accumulates in perinuclear spaces as aggresome-bodies in COPD lung tissues of tobacco smokers and severe emphysema subjects, compared with non-emphysema or nonsmoker controls. Next, Beas2b cells and C57BL/6 mice were exposed to either cigarette smoke extract (CSE) or subchronic-CS (sc-CS), followed by treatment with potent TFEB-inducing drug, gemfibrozil (GEM, or fisetin as an alternate), to experimentally verify the role of TFEB in COPD. Our in vitro results indicate that GEM/fisetin-mediated TFEB induction significantly (p?<?0.05) decreases CSE-induced autophagy-impairment (Ub/LC3B reporter and autophagy flux assay) and resulting aggresome-formation (Ub/p62 coexpression/accumulation; immunoblotting and staining) by controlling reactive oxygen species (ROS) activity. Intriguingly, we observed that CS induces TFEB accumulation in the insoluble protein fractions of Beas2b cells, which shows a partial rescue with GEM treatment. Moreover, TFEB knockdown induces oxidative stress, autophagy-impairment, and senescence, which can all be mitigated by GEM-mediated TFEB induction. Finally, in vivo studies were used to verify that CS-induced autophagy-impairment (increased Ub, p62, and valosin-containing protein in the insoluble protein fractions of lung/cell lysates), inflammation (interleukin-6 [IL-6] levels in bronchoalveolar lavage fluid and iNOS expression in lung sections), apoptosis (caspase-3/7), and resulting emphysema (hematoxylin and eosin [H&E]) can be controlled by GEM-mediated TFEB induction (p?<?0.05).InnovationCS exposure impairs autophagy in COPD-emphysema by inducing perinuclear localization of master autophagy regulator, TFEB, to aggresome-bodies.ConclusionTFEB-inducing drug(s) can control CS-induced TFEB/autophagy-impairment and COPD-emphysema pathogenesis. Antioxid. Redox Signal. 27, 150-167.