Carbon monoxide provides antioxidant protection in hepatic sinusoids during a remote inflammatory stress by reducing carbonylated MnSOD

Abstract

Although the anti‐inflammatory benefits of exogenous CO are well recognized, its antioxidant potential remains unknown. We examined the role of CO in regulating hepatic oxidant generation using bilateral hindlimb ischemia/reperfusion (I/R) as a model of systemic inflammation. Immediately following the onset of I/R, mice were treated with exogenous CO (methylene chloride or gaseous CO). Bilateral hindlimb I/R caused significant liver damage and lipid peroxidation. In vivo digital microscopy with the oxidant‐sensitive probe dihydrorhodamine confirmed the generation of hepatic oxidants. Treatment with CO significantly reduced all aspects of liver damage and oxidant formation. Due to its chemistry, CO is not likely a direct oxidant scavenger. Thus we investigated whether the antioxidant benefit of exogenous CO occurred via regulation of manganese superoxide dismutase (MnSOD) activity. As with direct I/R, MnSOD protein expression was unchanged yet its activity was diminished. Concomitant to this functional MnSOD demise was an increase in its carbonylation ‐ an inactivating oxidative protein modification. Treatment with CO reduced the carbonylation of MnSOD and restored its activity. These results suggest that exogenous CO indirectly reduces the hepatic oxidant stress that accompanies a remote inflammatory insult by diminishing MnSOD carbonylation, and thereby restoring MnSOD activity.