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Ke B, Buelow R, Shen XD, Melinek J, Amersi F, Gao F, Ritter T, Volk HD, Busuttil RW, Kupiec-Weglinski JW: Heme oxygenase 1 gene transfer prevents CD95/Fas ligand-mediated apoptosis and improves liver allograft survival via carbon monoxide signaling pathway. Hum Gene Ther. 2002 Jul 1;13(10):1189-99.
Apoptosis via the CD95/FasL (CD95L) pathway plays an important role in allograft rejection. Heme oxygenase 1 (HO-1), a stress-responsive cytoprotective molecule, may be essential in preventing graft rejection. We used Ad-HO-1 gene transfer to analyze HO-1-mediated effects in a rat allogeneic orthotopic liver transplantation (OLT) model. The cytotoxicity to Fas-bearing YAC-1 target cells and frequency of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive (TUNEL (+)) cells in vitro were diminished in Ad-CD95L + Ad-HO-1-transfected cells, as compared with Ad-CD95L + Ad-beta-gal controls (p < 0.001). AdHO-1 gene transfer prevented <10-day rejection of dark agouti (DA) livers in Lewis (LEW) rats (survival > 32 days), and diminished apoptosis. Unlike Ad-beta-gal OLTs, which showed signs of severe acute rejection, OLTs in the Ad-HO-1 group exhibited mild to moderate rejection and improved function. These beneficial effects were abrogated after adjunctive treatment with tin protoporphyrin (SnPP), an HO-1 antagonist. Intragraft expression of HO-1 and antiapoptotic gene products (Bcl-xl/Bag-1) was enhanced in Ad-HO-1-transduced OLTs, in association with selectively depressed expression of helper T cell type 1 cytokines (interleukin 2 and interferon gamma), as compared with Ad-beta-gal controls. To deliver CO, one of the downstream HO-1 mediators, allogeneic OLT recipients were exposed to methylene chloride. Such treatment prolonged survival to > 47 days, diminished apoptosis, and preserved hepatic architecture/function. Thus, Ad-HO-1 gene transfer prevents CD95/FasL-mediated apoptosis, and significantly prolongs allogeneic OLT survival via a downstream HO-1-CO signaling pathway. |
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