Abstract
Previously, we have shown that primary afferent sensory neurons are necessary for disease activity in T cell-mediated immune hepatitis in mice. In the present study, we analyzed the possible role of substance P (SP), an important proinflammatory neuropeptide of these nerve fibers, in an in vivo mouse model of liver inflammation. Liver injury was induced by bacterial lipopolysaccharide (LPS) ind-galactosamine (GalN)-sensitized mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment down-regulated circulating levels of the proinflammatory cytokines tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) and protected mice from GalN/LPS-induced liver injury. Likewise, pretreatment of mice with antagonists of the SP-specific neurokinin-1 receptor (NK-1R), i.e., (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) and (2S,3S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine (L-733,060), dose dependently protected mice from GalN/LPS-induced liver injury. The presence of the NK-1R in the murine liver was demonstrated by reverse transcription-polymerase chain reaction, sequence analysis, and immunocytochemistry. NK-1R blockade reduced inflammatory liver damage, i.e., edema formation, neutrophil infiltration, hepatocyte apoptosis, and necrosis. To get further insight into the mechanism by which receptor blockade attenuated GalN/LPS-induced liver damage, we analyzed plasma levels and intrahepatic expression of TNFα, IFNγ, interleukin (IL)-6, and IL-10. NK-1R blockade clearly inhibited GalN/LPS-induced production of TNFα and IFNγ, whereas synthesis of the hepatoprotective cytokines IL-6 and IL-10 was increased. NK-1 receptor antagonists might be potent drugs for treatment of inflammatory liver disease, most likely by inhibiting SP effects.
Footnotes
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This work was supported by the Deutsche Forschungsgemeinschaft (DFG) Grant NE 534/1-1.
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DOI: 10.1124/jpet.102.043539
- Abbreviations:
- SP
- substance P
- NF-κB
- nuclear factor-κB
- NK-1R
- neurokinin-1 receptor
- LPS
- lipopolysaccharide
- GalN
- d-galactosamine
- TNFα
- tumor necrosis factor-α
- IFNγ
- interferon-γ
- IL
- interleukin
- CP-96,345
- (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine
- L-733,060
- (2S,3S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine
- ALT
- alanine aminotransferase
- AST
- aspartate aminotransferase
- NPC
- nonparenchymal liver cells
- RT-PCR
- reverse transcription-polymerase chain reaction
- bp
- base pair
- DTT
- dithiothreitol
- AP-1
- activator protein-1
- TBS
- Tris-buffered saline
- SR 140333
- nolpitantium
- Received August 27, 2002.
- Accepted December 19, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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