Vagus Nerve Attenuates Hepatocyte Apoptosis upon Ischemia–Reperfusion via α7 Nicotinic Acetylcholine Receptor on Kupffer Cells in Mice

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Hepatic ischemia–reperfusion (HIR) injury is a complication of liver surgery. As much as 50% of hepatocytes undergo apoptosis within the first 24 h of reperfusion. The neurotransmitters of the vagus nerve can activate α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages. The function of Kupffer cells (KCs) determines HIR injury. We hypothesize that the vagus nerve could attenuate HIR-induced hepatocyte apoptosis by activating α7nAChR on KCs.


Hepatic vagotomized C57BL/6J mice, KC-eliminated C57BL/6J mice, and α7nAChR−/− mice were used for HIR. Primary KCs and hepatocytes were subjected to hypoxia/reoxygenation (HR). Liver injury, hepatocyte apoptosis, reactive oxygen species (ROS) production, and soluble CD163 were measured.


Hepatic vagotomy and α7nAChR−/− caused higher levels of alanine transaminase and liver caspase-3 and -8 activity by HIR. Activating α7nAChR attenuated these changes in wild-type but not in the α7nAChR−/− mice. Furthermore, activating α7nAChR diminished hepatic injury and reduced liver apoptosis by HIR in vagotomized mice. In vitro, activating α7nAChR reduced apoptosis of hepatocytes cocultured with KCs that suffered HR. Similar to the effects by catalase, activating α7nAChR on KCs reduced ROS and H2O2 by HR. The supernatant from KCs, with α7nAChR activated or catalase treated, prevented hepatocyte apoptosis by HR. Finally, KC elimination reduced HIR-induced H2O2 production in mice. Activating α7nAChR significantly attenuated soluble CD163 both in mice by HIR (serum: 240 ± 34 vs. 446 ± 72; mean ± SD; n = 8; P < 0.01) and in KCs by HR (supernatant: 4.23 ± 0.06 vs. 5.60 ± 0.18; n = 3; P < 0.01).


The vagus nerve could minimize HIR-induced liver apoptosis through activating α7nAChR on KCs possibly by preventing their excessive ROS production.

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