The current pharmacologic and surgical therapies for portal hypertension a notoriously frustrating, often fatal, clinical complication of liver cirrhosis, have limited success due to the lack of clear understanding of its pathophysiology. Our work strongly indicates a major role of endothelin-1 (ET-1), a powerful vasoconstrictor, mitogen and fibrogen, in these pathologies. We observed progressive increases in hepatic ET-1 and its receptors during carbon tetrachloride (CC14)-induced cirrhosis in rats, and in cirrhotic humans. We demonstrated that a ET-1 receptor antagonist TAK-044 ameliorates portal hypertension and hepatic injury in CC14-treated rats. Further, we have shown that ET-1 stimulates the synthesis of a potent fibrogenic agent transforming growth factor-beta1, and exerts contractile and fibrogenic effects in perisinusoidal stellate cells. Stellate cells, the physiologic regulators of hepatic architecture and vascular tone, proliferate and transform into highly contractile and excessively fibrogenic myofibroblasts during liver cirrhosis. ET-1 also stimulates synthesis of a potent hepatic vasoconstrictor and systemic vasodilator platelet-activating factor (PAF) in Kupffer cells. PAF has been suggested to play a major role in hemodynamic abnormalities associated with cirrhosis. These observations indicate that interactions between ET-1, stellate cells and Kupffer cells are the major mechanism in the pathogenesis and complications of liver cirrhosis. Therefore, we propose to distinguish precise sites of changes in ET-1 and its receptors during the development of CC14-induced cirrhosis using the techniques of immunohistochemistry, in situ hybridization and cell fractionation. We will also delineate the mechanisms of (1) the elevated ET-1 levels during the development of cirrhosis; (2) the actions of ET-1 in causing structural and functional changes in stellate cells; and (3) the interactions between ET-1 and Kupffer cells with specific focus on PAF synthesis. Finally, we propose to evaluate the therapeutic potential of ET-1 receptor antagonists by administering them to rats (a) during the entire period of CC14 treatment; (b) from the time of transition between fibrosis and cirrhosis; and (c) after the development of cirrhosis to ascertain amelioration or reversal of the pathologic process. Thus, in addition to the determination of the molecular mechanisms of the role of ET-1 in liver cirrhosis, this investigation will provide valuable information for the development of appropriate therapeutic strategies for liver cirrhosis and its complications.
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