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Compartmentalized Expression of c-FLIP in Lung Tissues of Patients with Idiopathic Pulmonary Fibrosis

¹ Program in Cell Biology, Department of Pediatrics, ² Interstitial Lung Disease Program, Department of Medicine, and ⁵Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, Colorado; ³ Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, ⁴ Department of Immunology, and ⁵ Department of Biostatistics, Informatics, Physiology and Biophysics, University of Colorado Denver School of Medicine, Denver, Colorado; and ⁶ Department of Internal Medicine, Kyungpook National University School of Medicine and University Hospital, Daegu, Korea

Correspondence and requests for reprints should be addressed to David W. H. Riches, Program in Cell Biology, Department of Pediatrics, National Jewish Health, Smith Building, Room A549, 1400 Jackson Street, Denver, CO 80206. E-mail: richesd{at}njhealth.org

Increased apoptosis of alveolar epithelial cells and impaired apoptosis of myofibroblasts have been linked to the pathogenesis of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). Fas, a death receptor of the TNF-receptor superfamily, has been implicated in apoptosis of both cell types, though the mechanisms are poorly understood. The goals of this study were: (1) to examine the localization of Fas-associated death-domain-like IL-1β-converting enzyme inhibitory protein (c-FLIP), an NF-B–dependent regulator of Fas-signaling, in lung tissues from IPF/UIP patients and control subjects; and (2) to compare c-FLIP expression with epithelial cell and myofibroblast apoptosis, proliferation, and NF-B activation. c-FLIP expression was restricted to airway epithelial cells in control lung tissues. In contrast, in patients with IPF/UIP, c-FLIP was also expressed by alveolar epithelial cells in areas of injury and fibrosis, but was absent from myofibroblasts in fibroblastic foci and from alveolar epithelial cells in uninvolved areas of lung tissue. Quantification of apoptosis and proliferation revealed an absence of apoptotic or proliferating cells in fibroblastic foci and low levels of apoptosis and proliferation by alveolar epithelial cells. Quantification of NF-B expression and nuclear translocation revealed strong staining and translocation in alveolar epithelial cells and weak staining and minimal nuclear translocation in myofibroblasts. These findings suggest that: (1) c-FLIP expression is induced in the abnormal alveolar epithelium of patients with IPF/UIP, (2) the resistance of myofibroblasts to apoptosis in patients with IPF/UIP occurs independently of c-FLIP expression, and (3) increased NF-B activation and c-FLIP expression by the alveolar epithelium may be linked.

Key Words: idiopathic pulmonary fibrosis • c-FLIP • lung, epithelium • myofibroblast

CLINICAL RELEVANCE Differential Fas-mediated apoptosis of alveolar epithelial cells and myofibroblasts is of fundamental importance to the development of idiopathic pulmonary fibrosis (IPF), though how these responses are controlled remains poorly understood. This work will further the understanding of the role of Fas-associated death-domain-like IL-1β-converting enzyme inhibitory protein (c-FLIP) in the regulation of apoptosis in IPF. In addition, induced c-FLIP expression may be an early marker of injury to the alveolar epithelium in patients with IPF.