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Epithelial Endoplasmic Reticulum Stress and Apoptosis in Sporadic Idiopathic Pulmonary Fibrosis

¹ University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany; ² Department of Thoracic Surgery, Vienna General Hospital, Vienna, Austria; ³ Department of Pathology, Justus-Liebig-University Giessen, Giessen, Germany; ⁴ Department of Pathology, University of Saarland, Homburg/Saar, Germany; and ⁵ Division of Pulmonary Biology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to Andreas Guenther, M.D., University of Giessen Lung Center (UGLC), Department of Internal Medicine II, Klinikstrasse 36, 35392 Giessen, Germany. E-mail: andreas.guenther{at}uglc.de

Rationale: The molecular pathomechanisms underlying idiopathic pulmonary fibrosis (IPF) are elusive, but chronic epithelial injury has recently been suggested as key event.

Objectives: We investigated the possible implication of endoplasmic reticulum (ER) stress–mediated apoptosis in sporadic IPF.

Methods: We analyzed peripheral explanted lung tissues from patients with sporadic IPF (n = 24), chronic obstructive pulmonary disease (COPD) (n = 9), and organ donors (n = 12) for expression of major ER stress mediators and apoptosis markers by means of immunoblotting, semiquantitative reverse transcription–polymerase chain reaction, immunohistochemistry, and the TUNEL method.

Measurements and Main Results: Compared with COPD and donor lungs, protein levels of ER stress mediators, such as processed p50 activating transcription factor (ATF)-6 and ATF-4 and the apoptosis-inductor CHOP (C/EBP-homologous protein), as well as transcript levels of spliced X-box binding protein (XBP)-1, were significantly elevated in lung homogenates and type II alveolar epithelial cells (AECIIs) of IPF lungs. Proapoptotic, oligomeric forms of Bax, which play a key role in ER stress–mediated apoptosis downstream of CHOP induction, as well as caspase-3 cleavage, could be detected in IPF lungs. By means of immunohistochemistry, exclusive induction of active ATF-6, ATF-4, and CHOP in AECIIs was encountered in IPF but not in COPD or donor lungs. Immunoreactivity was most prominent in the epithelium near dense zones of fibrosis and fibroblast foci, where these ER stress markers colocalized with markers of apoptosis (TUNEL, cleaved caspase-3).

Conclusions: Severe ER stress response in the AECIIs of patients with sporadic IPF may underlie the apoptosis of this cell type and development of fibrosis in this disease.

Key Words: interstitial lung disease • lung fibrosis • type II alveolar epithelial cell • X-box binding protein-1 • C/EBP-homologous protein

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject No data are available concerning the underlying reasons for apoptosis in the alveolar epithelium of patients with idiopathic pulmonary fibrosis. What This Study Adds to the Field Severe endoplasmic reticulum stress of type II alveolar epithelial cells represents a major reason for apoptosis of this cell type in sporadic idiopathic pulmonary fibrosis.

 

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Stress in the ER (Endoplasmic Reticulum): A Matter of Life and Death for Epithelial Cells

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