This Article Full Text Full Text (PDF) All Versions of this Article: 2007-0221OCv1 38/5/541    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kelsen, S. G. Articles by Merali, S. PubMed PubMed Citation Articles by Kelsen, S. G. Articles by Merali, S.

Cigarette Smoke Induces an Unfolded Protein Response in the Human Lung

A Proteomic Approach

² Department of Biochemistry and ¹ Department of Medicine, Division of Pulmonary Critical Care and Pulmonary Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Steven G. Kelsen, M.D., 761 Parkinson Pavilion, Temple University Hospital, 3401 N. Broad Street, Philadelphia, PA 19140. E-mail: kelsen{at}temple.edu

Cigarette smoking, which exposes the lung to high concentrations of reactive oxidant species (ROS) is the major risk factor for chronic obstructive pulmonary disease (COPD). Recent studies indicate that ROS interfere with protein folding in the endoplasmic reticulum and elicit a compensatory response termed the "unfolded protein response" (UPR). The importance of the UPR lies in its ability to alter expression of a variety of genes involved in antioxidant defense, inflammation, energy metabolism, protein synthesis, apoptosis, and cell cycle regulation. The present study used comparative proteomic technology to test the hypothesis that chronic cigarette smoking induces a UPR in the human lung. Studies were performed on lung tissue samples obtained from three groups of human subjects: nonsmokers, chronic cigarette smokers, and ex-smokers. Proteomes of lung samples from chronic cigarette smokers demonstrated 26 differentially expressed proteins (20 were up-regulated, 5 were down-regulated, and 1 was detected only in the smoking group) compared with nonsmokers. Several UPR proteins were up-regulated in smokers compared with nonsmokers and ex-smokers, including the chaperones, glucose-regulated protein 78 (GRP78) and calreticulin; a foldase, protein disulfide isomerase (PDI); and enzymes involved in antioxidant defense. In cultured human airway epithelial cells, GRP78 and the UPR-regulated basic leucine zipper, transcription factors, ATF4 and Nrf2, which enhance expression of important anti-oxidant genes, increased rapidly (< 24 h) with cigarette smoke extract. These data indicate that cigarette smoke induces a UPR response in the human lung that is rapid in onset, concentration dependent, and at least partially reversible with smoking cessation. We speculate that activation of a UPR by cigarette smoke may protect the lung from oxidant injury and the development of COPD.

Key Words: oxidant defense • lung injury • COPD

CLINICAL RELEVANCE Chronic cigarette smoking induces an endoplasmic reticulum stress response in the human lung termed the unfolded protein response. Failure of this compensatory system in some cigarette smokers may contribute to the development of chronic obstructive pulmonary disease.