Inhibition of Hepatic Stellate Cell Proliferation and Activation by the Semisynthetic Analogue of Fumagillin Tnp–470 in Rats

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Abstract
Proliferation and activation of hepatic stellate cells (HSCs) are critical steps for the development of postnecrotic fibrosis in the liver. The present study aimed to reveal the inhibitory effect of the semisynthetic analogue of fumagillin TNP–470 on these events for its possible use as an antifibrogenic agent. Rat models of carbon tetrachloride (CCl4)– and dimethylnitrosamine–induced hepatic fibrosis were used for an in vivo study. In both models, the fibrotic area was considerably decreased by concurrent repetitive subcutaneous injections of 30 mg/kg body weight of TNP–470. In CCl4–induced fibrosis, factor VIII–related antigen–positive blood vessels, desmin–, or α–smooth muscle actin (αSMA)–positive mesenchymal cells, bromodeoxyuridine (BrdU)–positive mesenchymal cells also decreased in number by treatment with TNP–470. In in vitro experiments, a supplement of 1,000 ng/mL TNP–470 suppressed BrdU incorporation and cyclins D1, D2, and E expression by cultured HSCs in the absence and/or presence of platelet–derived growth factor (PDGF). Expression of HSC activation markers, i.e., αSMA and PDGF receptor β, was also suppressed. The present results indicate that TNP–470 inhibits HSC proliferation by blocking the cell–cycle transition from G1 to S and HSC activation, and, as the consequence, prevents the progression of hepatic fibrosis, probably being coupled with its antiangiogenic effect.