The Journal of Experimental Medicine
IN Cell Analyzer 2000
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Published 1 December 2003. doi:10.1084/jem.20031003
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© Rockefeller University Press, 0022-1007/2003/12/1707 $5.00
The Journal of Experimental Medicine, Volume 198, Number 11, 1707-1716

Carbon Monoxide Protects against Liver Failure through Nitric Oxide–induced Heme Oxygenase 1

Brian S. Zuckerbraun1, Timothy R. Billiar1, Sherrie L. Otterbein2, Peter K.M. Kim1, Fang Liu2, Augustine M.K. Choi2, Fritz H. Bach3 and Leo E. Otterbein2

1 Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
2 Division of Pulmonary and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
3 Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215

Address correspondence to Leo E. Otterbein, Division of Pulmonary and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Montefiore University Hospital 628 NW, Pittsburgh, PA 15213. Phone: (412) 802-3196; Fax: (412) 692-2260; email: otterbeinl{at}msx.upmc.edu; or Timothy R. Billiar, Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Presbyterian Hospital F1200, Pittsburgh, PA 15213. Phone: (412) 647-1749; Fax: (412) 647-3247; email: billiartr{at}msx.upmc.edu

Carbon monoxide (CO) and nitric oxide (NO) each have mechanistically unique roles in various inflammatory disorders. Although it is known that CO can induce production of NO and that NO can induce expression of the cytoprotective enzyme heme oxygenase 1 (HO-1), there is no information whether the protective effect of CO ever requires NO production or whether either gas must induce expression of HO-1 to exert its functional effects. Using in vitro and in vivo models of tumor necrosis factor {alpha}–induced hepatocyte cell death in mice, we find that activation of nuclear factor {kappa}B and increased expression of inducible NO are required for the protective effects of CO, whereas the protective effects of NO require up-regulation of HO-1 expression. When protection from cell death is initiated by CO, NO production and HO-1 activity are each required for the protective effect showing for the first time an essential synergy between these two molecules in tandem providing potent cytoprotection.

Key Words: carbon monoxide • nitric oxide • heme oxygenase • iNOS • hepatitis

Abbreviations used in this paper: ActD, actinomycin-D; ALT, alanine aminotransferase; APAP, acetaminophen; A.U., arbitrary units; CM, cytokine mixture; CO, carbon monoxide; CoPP, cobalt protoporphyrin; D-gal, D-galactosamine; EMSA, electrophoretic mobility shift assay; H&E, hematoxylin and eosin; HO-1, heme oxygenase 1; iNOS, inducible nitric oxide synthase; L-NIL, L-N6-(1-iminoethyl)-lysine-dihydrochloride; L-NIO, L-N5-(1-iminoethyl)-ornithine-2HCl; NF, nuclear factor; NO, nitric oxide; SNAP, s-nitroso-N-acetyl-penicillamine; SnPP, tin protoporphyrin; V-PYRRO, O2-vinyl 1-(pyrrolidin-1-yl) diazen-1-ium-1,2-diolate.


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