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Gastroenterology. 2008 Jun;134(7):2122-31. doi: 10.1053/j.gastro.2008.03.005. Epub 2008 Mar 8.

The hepatic vagus nerve attenuates Fas-induced apoptosis in the mouse liver via alpha7 nicotinic acetylcholine receptor.

Author information

1
Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Abstract

BACKGROUND & AIMS:

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.

PMID:
18439427
DOI:
10.1053/j.gastro.2008.03.005
[Indexed for MEDLINE]

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