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DOI: 10.1055/s-2006-951165
Carbon monoxide, a natural product of HO enzymatic action, rescues mice from fulminant hepatitis
Heme oxygenase (HO) enzymes cleave the pro-oxidant heme molecule into carbon monoxide (CO), ferrous iron, and biliverdin, which is subsequently converted to bilirubin. Among three identified isoforms of HO, HO-1 is inducible and widely expressed under stress conditions in parenchymal and non-parenchymal cells of liver. In this study, we showed that HO-1 was protective against fulminant hepatitis in a siRNA experiment. HO-1 suppressed TNFa-induced primary hepatocyte apoptosis mediated by one of its catalytic products, CO. HO-1/CO up-regulated Bcl-xL expression through the activation the p38 MAPK and AKT pathways in an ATP-dependent manner. The increase of cellular ATP levels stimulated by CO was dependent on the activation of sGC (ODQ sensitive). The hepatic ATP levels increased significantly after CO exposure and were associated with a marked reduction of apoptotic cells in the liver as detected at 4 hours after injection of TNFa in GalN-sensitized mice. To evaluate the therapeutic potential of CO, we exposed mice to CO (500 ppm) for one hour after induction of fulminant hepatitis by LPS/GalN or concanavalin A. CO exposure significantly rescued the mice from fulminant hepatitis when CO was given for one hour at 1 to 6 hours after the LPS/GalN or concanavalin A injection: 20–90% of mice given CO survived for more than 7 days, whereas control mice died within 12 hours. Our demonstration of the importance of the energy status to maximize an anti-apoptotic response provides a new insight into HO-1-mediated cytoprotection. The overall data suggest that CO might be a useful therapy for fulminant hepatitis.