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  • Title: Activation of the cholinergic anti-inflammatory pathway by nicotine attenuates hepatic ischemia/reperfusion injury via heme oxygenase-1 induction.
    Author: Park J, Kang JW, Lee SM.
    Journal: Eur J Pharmacol; 2013 May 05; 707(1-3):61-70. PubMed ID: 23535606.
    Abstract:
    Hepatic ischemia/reperfusion (I/R) elicits an excessive inflammatory response, posing a lethal threat to the host. Local inflammation may be regulated by the vagus nerve and activation of the nicotinic acetylcholine receptors may also suppress peripheral inflammation. We have previously demonstrated that heme oxygenase-1 (HO-1) protects the liver against I/R injury by modulating proinflammatory mediators. Here, we investigate the cytoprotective mechanisms of nicotine, a nicotinic acetylcholine receptor agonist, against liver injury caused by I/R. Mice were subjected to 60 min of ischemia followed by 3h of reperfusion. Nicotine (0.1, 0.3 and 1 mg/kg) and vehicle (saline) were administered intraperitoneally 20 min prior to ischemia. Serum alanine aminotransferase activity and lipid peroxidation levels increased after reperfusion, while total glutathione content decreased. These changes were markedly attenuated by nicotine. The levels of HO activity and HO-1 protein expression increased after reperfusion, and nicotine markedly augmented these increases. Serum levels of high mobility group box 1 and tumor necrosis factor-α increased after reperfusion, and nicotine prevented these increases. The nuclear translocation of NF-E2-related factor 2 and phosphorylation of both phosphatidyl inositol 3-kinase and Akt increased; nicotine also augmented these increases. The protein expression of nuclear factor-κB increased and nicotine attenuated this increase. Methyllycaconitine, a selective α7 nicotinic acetylcholine receptor antagonist, abolished these effects of nicotine. Furthermore, zinc protoporphyrin, an HO-1 inhibitor, also reversed the observed effects of nicotine. Our findings suggest that activation of α7 nicotinic acetylcholine receptor by nicotine ameliorates I/R-induced liver injury, and that this protection is likely due to inhibition of the inflammatory response through HO-1 induction.
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