• Martina Korfei, Clemens Ruppert, Poornima Mahavadi, Ingrid Henneke, Philipp Markart, Miriam Koch, Gyoergy Lang, Ludger Fink, Rainer-Maria Bohle, Werner Seeger, Timothy E Weaver, and Andreas Guenther.
• University of Giessen Lung Center, Department of Internal Medicine II, Klinikstrasse 36, 35392 Giessen, Germany.
• Am. J. Respir. Crit. Care Med. 2008 Oct 15; 178 (8): 838-46.

RationaleThe molecular pathomechanisms underlying idiopathic pulmonary fibrosis (IPF) are elusive, but chronic epithelial injury has recently been suggested as key event.ObjectivesWe investigated the possible implication of endoplasmic reticulum (ER) stress-mediated apoptosis in sporadic IPF.MethodsWe 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 ResultsCompared 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).ConclusionsSevere 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.

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