Carbon monoxide has antioxidative properties in the liver involving p38 MAP kinase pathway in a murine model of systemic inflammation.

OBJECTIVE

Reactive oxygen species (ROS) are important in the hepatocellular injury process during a systemic inflammation. We examined the role of carbon monoxide (CO) on the hepatic generation of ROS with in-vivo and in-vitro models of systemic inflammation.

METHODS

Using a murine model of bilateral hindlimb ischemia-reperfusion (I/R) we examined the effect of CO treatment on hepatic ROS formation, oxidative status, and cell injury. Cultured HUVEC were used to investigate intracellular pathways.

RESULTS

CO treatment reduced hepatic lipid peroxidation, re-established total hepatic glutathione and glutathione disulfide (GSH/GSSG) levels and reduced hepatocellular injury. Inhibition of heme oxygenase (HO) during treatment with CO during hindlimb I/R failed to alter the antioxidant qualities provided by CO. The production of ROS after tumor necrosis factor-α (TNF-α) stimulation in HUVEC was diminished after exposure to CO. Treatment with CO during HO inhibition reduced both ROS formation and cell injury. Inhibiting the p38 MAPK (mitogen-activated protein kinase) pathway with pyridinyl imidazol (SB203580) revealed that the antioxidant potential of CO involved the activation of p38 MAPK.

CONCLUSIONS

CO has direct antioxidant potential independently of any HO activity during systemic inflammation. The antioxidant effects afforded by CO involve the activation of the p38 MAPK pathway.