title: The hepatic vagus nerve attenuates Fas-induced apoptosis in the mouse liver via alpha7 nicotinic acetylcholine receptor.
abstract: OBJECTIVE
  Although accumulating evidence has recently shown that the efferent vagus nerve attenuates systemic inflammation, it remains unclear whether or not the vagus nerve can affect Fas-induced liver apoptosis. We investigated the effect of the vagus nerve by using a selective hepatic vagotomy.
  
  
  METHODS
  We assessed the mortality and apoptosis in Fas-induced fulminant hepatitis in sham-operated and vagotomized male C57BL/6 mice. To determine how the nerve influences hepatocyte apoptosis, hepatitis was preceded by pretreatment with nicotine; PNU-282987, an alpha7 nicotinic acetylcholine receptor (AChR) agonist; liposome-encapsulated dichloromethylene diphosphonate (lipo-Cl(2)MDP), a macrophage eliminator; and Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP), an oxidative inhibitor.
  
  
  RESULTS
  Mortality in the vagotomized mice was significantly higher than that in the sham-operated mice following intravenous administration with the anti-Fas antibody Jo-2. This result was also supported by the data from both terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling and caspase-3 assay, in which vagotomized livers showed a significant elevation in the number of apoptotic hepatocytes and increased caspase-3 activity following Jo-2 treatment compared with the sham-operated livers. Supplementation with nicotine and PNU-282987 dose dependently inhibited this detrimental effect of the vagotomy. Moreover, the vagotomy-triggered exacerbation of Fas-induced hepatitis was completely blocked by lipo-Cl(2)MDP. Similarly, pretreatment with MnTBAP also completely suppressed the vagotomy-triggered exacerbation.
  
  
  CONCLUSIONS
  The hepatic vagus nerve appears to play an important role in attenuating Fas-induced hepatocyte apoptosis through alpha7 nicotinic AChR, perhaps by causing the Kupffer cells to reduce their generation of an excessive amount of reactive oxygen species.
authors.affiliation: Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hiramoto
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Chida
authors.forename: Junko
authors.initials: J
authors.lastname: Sonoda
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Yoshihara
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sudo
authors.forename: Chiharu
authors.initials: C
authors.lastname: Kubo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006505:Hepatitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000294:innervation* / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008697:Methane / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014628:Vagotomy; D014630:Vagus Nerve / Q000378:metabolism* / Q000601:surgery; D064569:alpha7 Nicotinic Acetylcholine Receptor; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000975:Antioxidants; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; C579166:Chrna7 protein, mouse; D004164:Diphosphonates; C118184:LE-Cl2MDP; D008665:Metalloporphyrins; D018722:Nicotinic Agonists; C498513:PNU-282987; D017382:Reactive Oxygen Species; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C411023:anti-Fas monoclonal antibody; D019014:fas Receptor; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D009538:Nicotine; C505409:Casp3 protein, mouse; D053148:Caspase 3; D008697:Methane