ANTIFIBROGENIC EFFECT OF A DELETION VARIANT OF HEPATOCYTE GROWTH-FACTOR ON LIVER FIBROSIS IN RATS

Hepatic fibrosis, which may lead to cirrhosis, is associated with most chronic liver diseases, Current therapies for hepatic fibrosis are, h owever, generally ineffective, In this report we assessed the efficacy of the treatment of hepatic fibrosis with a naturally occurring delet ion variant of hepatocyte growth factor (dHGF). The administration of dHGF increased liver weight and suppressed the increase of hepatic col lagen content in rats treated with dimethylnitrosamine (DMN) to induce hepatic fibrosis, Furthermore, dHGF exerted its mitogenic and antifib rogenic activities even after the liver fibrosis had been established with DMN, Northern blot analysis showed that dHGF suppressed the incre ase of messenger RNA (mRNA) levels of procollagen alpha 2(I), alpha 1( III), alpha 1(IV), transforming growth factor beta(1) (TGF-beta(1)), d esmin (a marker of hepatic lipocytes), and alpha-smooth muscle (sm)act in (a marker of activated hepatic lipocytes), In addition to suppressi ng the elevated TGF-beta(1) mRNA level in hepatic fibrosis, dHGF had a potent ability to decrease TGF-beta(1) mRNA level even in a normal li ver, Immunohistochemical analysis revealed that desmin-positive cells and alpha-sm-actin-positive cells were increased in the hepatic fibros is, whereas neither cells were seen in livers of DMN-treated rats give n dHGF, We conclude that dHGF prevents and improves the DMN-induced he patic fibrosis in rats by reducing mRNA levels of procollagens and TGF -beta(1), by inhibiting an activation of hepatic lipocytes, and by sti mulating liver regeneration. dHGF may be useful for and applicable to the treatment of fibrosis in chronic liver diseases.