Erythropoietin inhibits respiratory epithelial cell apoptosis in a model of acute lung injury.
Fas-mediated apoptosis of the alveolar epithelium is important in the pathogenesis of acute respiratory distress syndrome. Erythropoietin (EPO) has cytoprotective properties in other organ systems, and is relatively deficient in critical illness. This study investigates a potential role for EPO in reducing apoptosis in a model of acute lung injury. Apoptosis was induced in human alveolar epithelial (A549) cells or normal human bronchial epithelial (NHBE) cells by Fas activation with CH-11 Fas-crosslinking antibody or by co-culture with polymorphonuclear neutrophils in a transwell system. The effect of recombinant human (rh)EPO on apoptosis was measured by poly(ADP-ribose) polymerase cleavage and cell death detection assay. The specific EPO-EPO receptor (EPOR)-mediated effect was determined using an EPO-blocking antibody or EPOR small interfering RNA. Expression of EPOR was demonstrated in A549, NHBE and normal human alveolar epithelium. Fas- and neutrophil-mediated apoptosis of A549 and NHBE cells was inhibited by rhEPO by a specific EPO-EPOR-mediated mechanism. This anti-apoptotic effect was associated with induction of a pro-apoptotic Bcl-xL/Bax ratio. EPO has cytoprotective properties in respiratory epithelium in an in vitro model, which may indicate a potential therapeutic role in acute lung injury.
MacRedmond
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Providence Healthcare Heart and Lung Institute, St Paul's Hospital, University of British Columbia, Vancouver, BC, Canada. rmacredmond@mrl.ubc.ca
Singhera
G K
GK
Dorscheid
D R
DR
D055371:Acute Lung Injury / Q000188:drug therapy*; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000378:metabolism*; D004921:Erythropoietin / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism
C491901:FAS protein, human; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D019014:fas Receptor; D004921:Erythropoietin