Critical Care Medicine  |   November 2016
Vagus Nerve Attenuates Hepatocyte Apoptosis upon Ischemia–Reperfusion via α7 Nicotinic Acetylcholine Receptor on Kupffer Cells in Mice
Author Notes
  • From the Department of Pharmacy, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China (M.N., F.H., T.Z., D.-J.L., F.-M.S.); and Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China (H.F., J.-K.C.).
  • Submitted for publication November 30, 2015. Accepted for publication July 20, 2016.
    Submitted for publication November 30, 2015. Accepted for publication July 20, 2016.×
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • M.N. and H.F. contributed equally to this work.
    M.N. and H.F. contributed equally to this work.×
  • Address correspondence to Dr. Shen: Department of Pharmacy, Shanghai Tenth People’s Hospital, Tongji University, 301 Middle Yanchang Road, Shanghai 200072, China. fumingshen@tongji.edu.cn. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Cardiovascular Anesthesia / Central and Peripheral Nervous Systems / Critical Care / Gastrointestinal and Hepatic Systems / Neurosurgical Anesthesia / Ophthalmologic Anesthesia
Critical Care Medicine   |   November 2016
Vagus Nerve Attenuates Hepatocyte Apoptosis upon Ischemia–Reperfusion via α7 Nicotinic Acetylcholine Receptor on Kupffer Cells in Mice
Anesthesiology 11 2016, Vol.125, 1005-1016. doi:10.1097/ALN.0000000000001309
Anesthesiology 11 2016, Vol.125, 1005-1016. doi:10.1097/ALN.0000000000001309
Abstract

Background: 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.

Methods: 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.

Results: 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).

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