The hepatic vagus nerve attenuates Fas-induced apoptosis in the mouse liver via alpha7 nicotinic acetylcholine receptor.
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.
Hiramoto
Tetsuya
T
Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Chida
Yoichi
Y
Sonoda
Junko
J
Yoshihara
Kazufumi
K
Sudo
Nobuyuki
N
Kubo
Chiharu
C
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*
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