| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 104 === Background and Aims:
Although carbon tetrachloride (CCl4) is widely used as an animal model of severe hepatic failure and the mechanisms have been arduously studied, the contribution of the sympathetic nerve system (SNS) in CCl4-induced acute liver injury remains controversial. In addition to being the primary organ involved in redox cycling, the liver is also one of the most highly innervated tissues in mammals. Although the SNS is known to modulate both liver regeneration and hepatic fibrosis, less is known regarding the role of the SNS in modulating the hepatic response to oxidative stress. Our aim was to establish the effect of sympathetic ablation in a mouse model of CCl4-induced acute hepatic injury and investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma.
Methods:
CCl4 injection was used to induce acute oxidative liver injury. The peripheral sympathetic nerve terminals of mice were ablated by intraperitoneal injection of a neurotoxin, 6-hydroxydopamine. Eight-week old wild-type C57Bl/6JNarl male mice exposure to CCl4 or vehicle were pretreated with or without sympathetic denervation. Development of liver injury, oxidative stress, hepatocyte ultra-structural damage, and inflammatory responses were investigated. A further set of mice was included for additional experiments to evaluate the effects of pharmacological inhibition of sympathetic activity by giving α and or β blockers prior to CCl4.
Results:
Mice treated with 6-hydroxydopamine displayed reduced tyrosine hydroxylase-positive fibers in the liver, realising chemical sympathectomy. Sympathectomized animals were protected from CCl4-induced hepatotoxicity. Chemical sympathectomy modulated the CCl4-induced inflammatory response within the liver. CCl4-induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist.
Conclusion
We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress and injury indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury.
|
|---|
