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

Brian S. Zuckerbraun, Timothy R. Billiar*, Sherrie L. Otterbein, Peter K.M. Kim, Fang Liu, Augustine M.K. Choi, Fritz H. Bach, Leo E. Otterbein

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

190 Scopus citations


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 α-induced hepatocyte cell death in mice, we find that activation of nuclear factor κB 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.

Original languageEnglish
Pages (from-to)1707-1716
Number of pages10
JournalJournal of Experimental Medicine
Issue number11
StatePublished - 1 Dec 2003
Externally publishedYes


  • Carbon monoxide
  • Heme oxygenase
  • Hepatitis
  • Nitric oxide
  • iNOS


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