Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 198, Issue 11, Pages 1707-1716Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20031003
Keywords
carbon monoxide; nitric oxide; heme oxygenase; iNOS hepatitis
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL058688, R01HL060234] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM044100] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL 58688, HL60234, R01 HL060234] Funding Source: Medline
- NIGMS NIH HHS [R01 GM044100, R01-GM-44100] Funding Source: Medline
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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 kappaB 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.
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