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


RESULTS
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.
Chen
Zhi-Hua
ZH
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Kim
Hong Pyo
HP
Sciurba
Frank C
FC
Lee
Seon-Jin
SJ
Feghali-Bostwick
Carol
C
Stolz
Donna B
DB
Dhir
Rajiv
R
Landreneau
Rodney J
RJ
Schuchert
Mathew J
MJ
Yousem
Samuel A
SA
Nakahira
Kiichi
K
Pilewski
Joseph M
JM
Lee
Janet S
JS
Zhang
Yingze
Y
Ryter
Stefan W
SW
Choi
Augustine M K
AM
D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000502:physiology*; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000473:pathology; D012907:Smoking; D014026:Nicotiana
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1