Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection

1 Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, 2 Department of Medicine, Division of Infectious Diseases, 3 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; 4 Department of Veterans Affairs Medical Cen...

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Published in:American journal of physiology. Lung cellular and molecular physiology 2008-06, Vol.294 (6), p.L1119-L1126
Main Authors: Lawson, William E, Crossno, Peter F, Polosukhin, Vasiliy V, Roldan, Juan, Cheng, Dong-Sheng, Lane, Kirk B, Blackwell, Thomas R, Xu, Carol, Markin, Cheryl, Ware, Lorraine B, Miller, Geraldine G, Loyd, James E, Blackwell, Timothy S
Format: Article
Language:English
Subjects:
alpha-Mannosidase - biosynthesis
Antigens, Viral - biosynthesis
Cells
Cells, Cultured
Cystic fibrosis
DNA-Binding Proteins - biosynthesis
Endoplasmic Reticulum - physiology
Glycoproteins - biosynthesis
Heat-Shock Proteins - biosynthesis
Herpes viruses
Herpesviridae Infections - complications
Herpesviridae Infections - physiopathology
Herpesvirus
Humans
Immunohistochemistry
Lungs
Molecular Chaperones - biosynthesis
Nuclear Proteins - biosynthesis
Pathology
Protein Folding
Proteins
Pulmonary Alveoli - ultrastructure
Pulmonary Fibrosis - complications
Pulmonary Fibrosis - physiopathology
Pulmonary Surfactant-Associated Protein C - genetics
Pulmonary Surfactant-Associated Protein C - physiology
Regulatory Factor X Transcription Factors
Stress, Physiological - physiopathology
Surfactants
Transcription Factors
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Summary:1 Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, 2 Department of Medicine, Division of Infectious Diseases, 3 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; 4 Department of Veterans Affairs Medical Center, Nashville, Tennessee; and 5 Hospital Universitari Germans Trias i Pujol, Badalona, Spain Submitted 13 September 2007 ; accepted in final form 31 March 2008 Recent evidence suggests that dysfunctional type II alveolar epithelial cells (AECs) contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Based on the hypothesis that disease-causing mutations in surfactant protein C ( SFTPC ) provide an important paradigm for studying IPF, we investigated a potential mechanism of AEC dysfunction suggested to result from mutant SFTPC expression: induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We evaluated biopsies from 23 IPF patients (including 3 family members with L188Q SFTPC mutations, 10 individuals with familial interstitial pneumonia without SFTPC mutations, and 10 individuals with sporadic IPF) and sections from 10 control lungs. After demonstrating UPR activation in cultured A549 cells expressing mutant SFTPC , we identified prominent expression of UPR markers in AECs in the lungs of patients with SFTPC mutation-associated fibrosis. In individuals with familial interstitial pneumonia without SFTPC mutations and patients with sporadic IPF, we also found UPR activation selectively in AECs lining areas of fibrotic remodeling. Because herpesviruses are found frequently in IPF lungs and can induce ER stress, we investigated expression of viral proteins in lung biopsies. Herpesvirus protein expression was found in AECs from 15/23 IPF patients and colocalized with UPR markers in AECs from these patients. ER stress and UPR activation are found in the alveolar epithelium in patients with IPF and could contribute to disease progression. Activation of these pathways may result from altered surfactant protein processing or chronic herpesvirus infection. lung; surfactant protein C; usual interstitial pneumonia; unfolded protein response Address for reprint requests and other correspondence: W. E. Lawson, Div. of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt Univ. School of Medicine, T-1218 MCN, Nashville, TN 37232-2650 (e-mail: william.lawson{at}vanderbilt.edu )
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.00382.2007