Background/Aims-A potential application of gliotoxin therapy for liver fibrosis was suggested by its apoptotic effect on fibrogenic activated stellate cells. We investigated if gliotoxin exerts similar effects on hepatic macrophages Kupffer cells.

Our results emphasize the role of ET-1 in chronic liver disease and strongly indicate the potential for ET-1 receptor antagonists in its treatment.

1 Physiologically, perisinusoidal hepatic stellate cells (HSC) are quiescent and store retinoids. During liver injury and in cell culture, HSC transform into proliferating myofibroblast-like cells that express a-smooth muscle actin (a-sma) and produce excessive amounts of extracellular matrix. During transformation (also known as activation), HSC are depleted of the retinoid stores, and their expression of the endothelin-1 (ET-1) system is increased. ET-1 causes contraction of transformed HSC and is implicated in their proliferation and fibrogenic activity. In order to understand the association between retinoids, ET-1 and the activation of HSC, we investigated the effect of 13-cisretinoic acid on the transformation of cultured HSC and the expression of ET-1 system. 2 HSC derived from normal rat liver were maintained for 10 -12 days in a medium supplemented with 5% serum and containing 2.5 mm retinoic acid without or with 50 nm ET-1 (ETa þ ETb agonist) or sarafotoxin S6c (ETb agonist). In another set of experiments, cells treated for 10 -12 days with vehicle (ethanol) or retinoic acid were challenged with ET-1 or sarafotoxin S6c, and various determinations were made at 24 h.