Mechanism of hepatic sympathetic action on potentiating liver injury and the involvement of cytokines.

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The effects of hepatic sympathetic nerves on acute liver damage and the involvement of cytokine were studied using perfused rat liver as ex vivo system.The results were as follows :1) Effects of hepatic nerve stimulation on acute liver damage : Rat livers were perfused in situ without recirculation under constant pressure after treatment with D-galactosamine to produce acute liver injury. Meassuring the activities of lactate dehydrogenase and aspartate aminotransferase in the effluent as markers of acute cell damage, electrical stimulation of hepatic nerves increased the leakage of these enzymes. Moreover, infusion of zymosan, an activator of kupffer cells, into the portal vein also increased the enzyme leakage like nerve stimulation. These result indicate that the activation of hepatic nerves potentiates acute liver injury and that hepatic non-parenchymal cells may be involved in the action of hepatic nerves.2) Noradrenaline overflow during nerve stimulation and receptor subtype : In … More perfused livers described above, noradrenaline overflow into the effluent was rapidly increased during nerve stimulation indicating that these nerves belong to sympathetic nervous system. On the other hand, the potentiation of acute liver damage caused by hepatic nerve stimulation was significantly inhibited by alpha-adrenergic blocker bunazosin hydrochloride, suggesting that the effects of hepatic sympathetic nerves are mainly mediated by alpha-adrenergic receptors.3) Bioassay of TNF-alpha output from perfused liver : Bioassy system of Tumor Necrosis Factor-alpha (TNF-alpha), Which is related with cell death of hepatocyte, was established using WEHI164-cell clone. TNF-alpha activity in the effluent was higher in galactosamine-treated liver than in normal liver. Moreover, electrical stimuration of hepatic sympathetic nerves rapidly increased TNF-alpha output in galactosamine-treated liver. These results suggest that production and release of TNF-alpha is increased in injured livers and regulated by hepatic sympathetic nerves, and that Kupffer cell is important for TNF-alpha production.4) Immunohistochemistry of TNF-alpha in the liver : Immunohistochemistry of TNF-alpha in the liver using anti-TNF-alpha antibodies showed that TNF-alpha was strongly stained in galactosamine-treated liver suggesting the increased production of this cytokine in injured liver.These results indicate that the activation of hepatic sympathetic nerves potentiates liver injury and that hepatic TNF-alpha has an important role in the action of hepatic nerves. Less