Journal Article

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

Pilewski, Joseph M., Stolz, Donna B., Lee, Janet S., Zhang, Yingze, Sciurba, Frank C., Ryter, Stefan W., Schuchert, Mathew J., Kim, Hong Pyo, Dhir, Rajiv, Chen, Zhi-Hua, Feghali-Bostwick, Carol, Nakahira, Kiichi, Choi, Augustine M. K., Yousem, Samuel A., Lee, Seon-Jin, Landreneau, Rodney J.

2008

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Air flow / Airflow / Airspace / Analysis / Animals / Apoptosis / Autophagy / Autophagy - physiology / B cells / Cell Biology/Cell Signaling / Cell Biology/Cellular Death and Stress Responses / Cell cycle / Cell death / Chronic obstructive lung disease / Chronic obstructive pulmonary disease / Cigarette smoke / Critical care / Development and progression / E2F protein / Early Growth Response Protein 1 - physiology / EGR-1 protein / Emphysema / Enlargement / Epithelial cells / Exposure / Fibroblasts / Gene expression / Genes / Genomes / Genotype & phenotype / Growth factors / Histone deacetylase / Hospitals / Humans / Inhibition / Lung diseases / Lungs / Medical schools / Medicine / Metabolism / Mice / Mice, Inbred C57BL / Microscopic analysis / Nicotiana / Obstructive lung disease / Pathogenesis / Pathology / Phagocytosis / Proteins / Pulmonary Disease, Chronic Obstructive - immunology / Pulmonary Disease, Chronic Obstructive - pathology / Respiratory Medicine/COPD and Allied Disorders / RNA polymerase / Rodents / Smoke / Smoking / Transcription factors / Womens health