The role of thromboxane A(2) in regulation of the hepatic portal circulation under pathological conditions

Thromboxane A2, a potent platelet aggregator and vasoconstrictor, has been implicated in many pathological conditions. In the present study, using isolated rat liver perfusion model, we investigated the role of TXA2 in the development of liver injury under stress conditions including cirrhosis, endotoxemia, and continuous hypothermic machine perfusion. We detected high level of TXB2 in perfusate, indicating increased production of TXA2 in the portal circulation, under these conditions. In addition, the higher level of TXA2 is associated with potentiated portal pressure and greater liver damage, indicated by increased levels of lactic dehydrogenase in the perfusate during perfusion. Thirdly, we observed that increased portal pressure was attenuated and liver injury was diminished when we inhibited the biosynthesis of TXA2. Finally, we found that Kupffer cells are the major source for TXA2 release in the liver under early cirrhosis and endotoxemia. Our data clearly demonstrate that TXA 2 is a critical vasoactive mediator in regulating portal vasculature tone. It is at least partially responsible for liver damage under these stress conditions. Moreover, our study suggests inhibition of TXA2 synthesis might be a potential therapeutic target for ameliorating liver damage under these conditions.