ENDOTHELIN-1 IS OVEREXPRESSED IN HUMAN CIRRHOTIC LIVER AND EXERTS MULTIPLE EFFECTS ON ACTIVATED HEPATIC STELLATE CELLS

Background & Aims: Endothelin (ET) 1 could be involved in the regulati on of hepatic microcirculation and in the development of portal hypert ension. The expression and distribution of ET-1 in normal and cirrhoti c liver tissue and its effects on hepatic stellate cells (HSCs), liver -specific pericytes, were investigated. Methods: ET-1 expression in li ver tissue was analyzed using in situ hybridization and immunohistoche mistry. Secretion of ET-1 by HSC was evaluated by radioimmunoassay. Ch anges in intracellular Ca2+ concentration and cell contraction were st udied using digital video imaging Specific binding of ET-1 was evaluat ed using self- and cross-displacement curves. Results: ET-1 expression was markedly enhanced in cirrhotic liver tissue, where activated HSCs were shown to be major sites of ET-1 synthesis, as confirmed by studi es performed on cultured human HSC. ET-1 exerted several biological ac tions on HSC, including mitogenicity, activation of mitogen-activated protein kinase, and a rapid increase in intracellular Ca2+ coupled wit h reversible cell contraction. All these effects appeared to be mediat ed by ET(A) receptors. Finally, the relative prevalence of ET(A) and E T(B) binding sites changed with the progressive phenotypical modulatio n of HSC. Conclusions: ET-1 may act as a paracrine and autocrine facto r for activated HSC and contribute to the increased resistance to port al flow in cirrhotic liver.