| Hepatic ischemia-reperfusion injury occurs in a number of clinical settings,including hemorrhagic shock,and liver surgery.The mechanism of liver injury remains far from full explanation.There is no single factor responsible for liver injury after its temporary ischemia and reperfusion. Apoptosis plays an important role in many diseases, such as hepatic fibrosis-renal tubular ectasia syndrome and hepatic ischemia reperfusion.α7 nicotinic acetylcholine receptor (α7nAChR) is widely expressed in neuronal and some non-neuronal cells (e.g., immune cells, endothelial cells, smooth muscle cells, bronchial epithelial cells, and skin keratinocytes) . Recent studies indicate that the nervous system, through vagus nerve, can modulate circulating TNF-α, IL-1βand IL-6 levels induced by endotoxin. This new mechanism termed"cholinergic anti-inflammatory pathway"is based on the release of acetylcholine (ACh), the principal neurotransmitter of the vagus nerve that inhibits the production of pro-inflammatory cytokines via itsα7nAChR in resident tissue macrophages. Our previous study found that expression ofα7nAChR in tissues of hypertension rats was down-regulated and chronic treatment of SHRs with theα7nAChR agonist PNU-282987 relieved end-organ damage. Recent studies emphasized the importance ofα7nAChR in physiological and pathological angiogenesis; activation ofα7nAChR in endothelial cells had proangiogenesis effects, and theα7nAChR agonist nicotine was demonstrated to increase capillary density in ischemic tissues in a rat model of myocardial infarction. Hiramoto indicated that the hepatic vagus nerve appeared to play an important role in attenuating Fas-induced hepatocyte apoptosis throughα7nAChR, perhaps by causing the kupffer cells to reduce their generation of an excessive amount of reactive oxygen species. However, there is no data available concerning the effect ofα7nAChR in hepatic ischemia reperfusion injury. We thus hypothesized thatα7nAChR plays a role in hepatic ischemia reperfusion injury.We have demonstrated that the antishock effect of anisodamine is intimately linked toα7nAChR-dependent cholinergic anti-inflammatory pathway. The mechanism of anisodamine action might be through blockade of muscarinic receptors and thus allowing more endogenous ACh binding to theα7nAChR. Atropine is often used before surgical operation to inhibit salivary secretion, generally it is administrated together with neostigmine to alleviate the adverse effects. In this study, we provided evidences that atropine benefited hepatic ischemia reperfusion injury through the activation of the α7nAChR.The first aim of this work is to demonstrate thatα7nAChR is expressed in the tissues of liver, and to investigate the roleα7nAChR in hepatic ischemia reperfusion injury. A reperfusion time-dependent hepatocellular injury occurred as was indicated by increased caspases and results from histological examination. It was found that the injury was associated with marked elevation of tissue-caspases. Compared with control, pre-ischemic treatment of mice with PNU-282987 or atropine and neostigmine significantly decreased tissue-caspases. Histological examination demonstrated that pretreatment with either PNU-282987 or atropine + neostigmine alleviated hepatic ischemia reperfusion injury. These suggested that hepatic injury in our experiment is related mainly to apoptosis, and activation ofα7nAChR inhibit this change.To investigate the role of activation ofα7nAChR in redox reaction during ischemia reperfusion, we determined the level of MDA and SOD. It was found that the level of MDA and activity of SOD significantly increased after 6h of reperfusion, pre-ischemic treatment of mice with PNU-282987 or atropine and neostigmine significantly decreased the level of MDA and increased activity of SOD.To evaluate the role of vagus nerve function in hepatic ischemia reperfusion injury, and demonstrate that the action of atropine + neostigmine is dependent on the vagus nerve, the hepatic vagus nerve was disconnected. Compared with sham-operated mice, vagotomy significantly increased the level caspase-3. Pretreatment with PNU-282987 inhibited this change induced by vagotomy. However, atropine and neostigmine administration did not influence the level of caspase-3. These data suggested that the hepatic vagus nerve plays an important role in hepatocyte apoptosis induced by ischemia reperfusion, which is mediated throughα7nAChR.Conclusion: Activation ofα7nAChR relieved hepatic ischemia reperfusion injury; atropine ameliorated hepatic ischemia reperfusion injury depending on the hepatic vagus nerve; the protective effect ofα7nAChR is related to the inhibition of cell apoptosis.
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