Carbon monoxide inhalation rescues mice from fulminant hepatitis through improving hepatic energy metabolism.
Heme oxygenase 1 (HO-1) enhances cellular antioxidative capability by increasing the cleavage of the endogenous and exogenous heme. Besides the biochemical activities of HO, the products of heme degradation significantly contribute to the cytoprotective effects of HO. Here, we show that HO-1 deficiency significantly increases the susceptibility of mice to apoptotic insults, whereas expression of HO-1 significantly increased the resistance of primary hepatocyte to apoptosis. This phenomenon was correlated with the production of one of its catalytic products-carbon monoxide (CO). Surprisingly, exposing the primary mouse hepatocyte to CO could improve the cellular energy metabolism in a soluble guanylyl cyclase-dependent manner. One-hour inhalation of low-dose CO enhanced the hepatic soluble guanylyl cyclase activities in mice. In parallel, the levels of hepatic adenosine triphosphate increased significantly and were associated with a marked reduction of TNF-alpha-induced apoptosis in the liver of D-galactosamine-sensitized mice. In addition, CO inhalation for 1 h significantly improved the survival of mice after initiation of fulminant hepatitis. Up to 90% of mice given CO survived for more than 7 days, whereas control mice died within 12 h. The data provide novel insight of CO-mediated cytoprotection.
Tsui
Tung-Yu
TY
Department of Surgery, University of Regensburg Medical Centre, Regensburg, Germany, and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. tung-yu.tsui@klinik.uni-regensburg.de
Obed
Aiman
A
Siu
Yeung-Tung
YT
Yet
Shaw-Fang
SF
Prantl
Lukas
L
Schlitt
Hans J
HJ
Fan
Sheung-Tat
ST
D000818:Animals; D000963:Antimetabolites / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D004734:Energy Metabolism / Q000187:drug effects*; D005688:Galactosamine / Q000633:toxicity; D006162:Guanylate Cyclase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
D000963:Antimetabolites; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D006162:Guanylate Cyclase