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LIVER AND BILIARY TRACT

Carbon monoxide activates NF-B via ROS generation and Akt pathways to protect against cell death of hepatocytes

¹Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and ²Department of Biology, Seoul National University Hospital, Seoul, Korea

Submitted 28 February 2007 ; accepted in final form 22 May 2008

Heme oxygenase overexpression or exogenous carbon monoxide (CO) protects against hepatocyte apoptosis and fulminant hepatitis. The prevention of hepatocyte apoptosis by CO has been shown to require activation of NF-B. The purpose of these investigations was to determine the mechanism of CO-induced hepatocyte NF-B activation and protection against apoptosis. Primary rat or mouse hepatocytes and Hep3B cells were utilized. CO exposure was performed at 250 parts per million. Main outcome measures included cell viability, reactive oxygen species (ROS) generation, and changes in the levels of the intracellular antioxidants glutathione and ascorbate. Western blotting was performed for phospho-Akt, total Akt, and IB. NF-B activation was determined by electrophoretic mobility shift assay and luciferase reporter assays. We found that CO treatment of hepatocytes prevents spontaneous apoptosis and leads to an increase in ROS production in association with Akt phosphorylation and IB degradation. CO did not increase ROS production in respiration-deficient (⁰) Hep3B cells. Both Akt phosphorylation and IB degradation can be inhibited by the addition of antioxidants. Furthermore, CO-induced NF-B activation is reversed by phosphatidylinositol 3-kinase (PI3-K) inhibitor (LY294002) or antioxidants. Additionally, prevention of spontaneous hepatocyte apoptosis by CO is reversed by PI3-K inhibition and antioxidants. In conclusion, these data implicate a survival pathway of CO-induced ROS, Akt phosphorylation, and NF-B activation in cultured hepatocytes. This pathway may prove to be important in maintenance of hepatic function in both physiological and pathophysiological conditions.

heme oxygenase; mitochondria; IB; antioxidant; PI3-kinase

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