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

Chen, ZH and Kim, HP and Sciurba, FC and Lee, SJ and Feghali-Bostwick, C and Stolz, DB and Dhir, R and Landreneau, RJ and Schuchert, MJ and Yousem, SA and Nakahira, K and Pilewski, JM and Lee, JS and Zhang, Y and Ryter, SW and Choi, AMK (2008) Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS ONE, 3 (10).

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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, Atg.7). 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-1-1- 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. © 2008 Chen et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Chen, ZH
Kim, HP
Sciurba, FCfcs@pitt.eduFCS
Lee, SJ
Feghali-Bostwick, C
Stolz, DBdonna.stolz@pitt.eduDSTOLZ
Dhir, Rdhir@pitt.eduDHIR
Landreneau, RJ
Schuchert, MJ
Yousem, SAyousem@pitt.eduYOUSEM
Nakahira, K
Pilewski, JMpilewski@pitt.eduPILEWSKI
Lee, JSjsl26@pitt.eduJSL26
Zhang, Yzhang3@pitt.eduZHANG3
Ryter, SW
Choi, AMK
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorHotchin, NeilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, Offices, or Units > Center for Biologic Imaging
Date: 2 October 2008
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 3
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0003316
Schools and Programs: School of Medicine > Cell Biology and Molecular Physiology
School of Medicine > Critical Care Medicine
Refereed: Yes
PubMed Central ID: PMC2552992
PubMed ID: 18830406
Date Deposited: 24 Jul 2012 18:47
Last Modified: 02 Feb 2019 21:55
URI: http://d-scholarship.pitt.edu/id/eprint/12999

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