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

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.

• Authors: Tetsuya Hiramoto, Yoichi Chida, Junko Sonoda, Kazufumi Yoshihara, Nobuyuki Sudo, Chiharu Kubo
• Journal: Gastroenterology (Gastroenterology) Vol. 134 Issue 7 Pg. 2122-31 (Jun 2008) ISSN: 1528-0012 [Electronic] United States
• PMID: 18439427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antioxidants
• Benzamides
• Bridged Bicyclo Compounds
• Chrna7 protein, mouse
• Diphosphonates
• LE-Cl2MDP
• Metalloporphyrins
• Nicotinic Agonists
• PNU-282987
• Reactive Oxygen Species
• Receptors, Nicotinic
• alpha7 Nicotinic Acetylcholine Receptor
• anti-Fas monoclonal antibody
• fas Receptor
• manganese(III)-tetrakis(4-benzoic acid)porphyrin
• Nicotine
• Casp3 protein, mouse
• Caspase 3
• Methane

Topics

• Animals
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Bridged Bicyclo Compounds (pharmacology)
• Caspase 3 (metabolism)
• Diphosphonates (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hepatitis (immunology, metabolism, pathology, prevention & control)
• Kupffer Cells (metabolism)
• Liver (drug effects, enzymology, innervation, pathology)
• Male
• Metalloporphyrins (pharmacology)
• Methane (pharmacology)
• Mice
• Mice, Inbred C57BL
• Nicotine (pharmacology)
• Nicotinic Agonists (pharmacology)
• Reactive Oxygen Species (metabolism)
• Receptors, Nicotinic (drug effects, metabolism)
• Reproducibility of Results
• Signal Transduction (drug effects)
• Time Factors
• Vagotomy
• Vagus Nerve (metabolism, surgery)
• alpha7 Nicotinic Acetylcholine Receptor
• fas Receptor (immunology, metabolism)