Antifibrogenic effect of a deletion variant of hepatocyte growth factor on liver fibrosis in rats

Abstract

Hepatic fibrosis, which may lead to cirrhosis, is associated with most chronic liver diseases. Current therapies for hepatic fibrosis are, however, generally ineffective. In this report we assessed the efficacy of the treatment of hepatic fibrosis with a naturally occurring deletion variant of hepatocyte growth factor (dHGF). The administration of dHGF increased liver weight and suppressed the increase of hepatic collagen content in rats treated with dimethylnitrosamine (DMN) to induce hepatic fibrosis. Furthermore, dHGF exerted its mitogenic and antifibrogenic activities even after the liver fibrosis had been established with DMN. Northern blot analysis showed that dHGF suppressed the increase of messenger RNA (mRNA) levels of procollagen α2(I), αl(III), α1(IV), transforming growth factor β1 (TGF‐β1), desmin (a marker of hepatic lipocytes), and α‐smooth muscle (sm)‐actin (a marker of activated hepatic lipocytes). In addition to suppressing the elevated TGF‐β1, mRNA level in hepatic fibrosis, dHGF had a potent ability to decrease TGF‐β1 mRNA level even in a normal liver. Immunohistochemical analysis revealed that desmin‐positive cells and α‐sm‐actin‐positive cells were increased in the hepatic fibrosis, whereas neither cells were seen in livers of DMN‐treated rats given dHGF. We conclude that dHGF prevents and improves the DMN‐induced hepatic fibrosis in rats by reducing mRNA levels of procollagens and TGF‐β1, by inhibiting an activation of hepatic lipocytes, and by stimulating liver regeneration. dHGF may be useful for and applicable to the treatment of fibrosis in chronic liver diseases.

Effect of Tetrandrine on Experimental Hepatic Fibrosis Induced by Bile Duct Ligation and Scission in Rats

“…It has been reported that pentoxifylline (Peterson & Neumeister 1996), oestradiol (Shimizu et al 1999), colchicines (Rodriguez et al 1998), prolyl 4-hydroxylase inhibitors (Bickel et al 1998), hepatocyte growth factor (Yasuda et al 1996), interferon-gamma ) have antifibrotic effects in animal models, but there are few promising therapeutics that are safe and effective in clinical situations. For several years we have screened candidates for antifibrotics from natural products, which have been used to treat liver diseases in traditional oriental medicine (Park et al 1997;Song et al 1998;Nan et al 2000;Park et al 2000a & b).…”

Adenosine reverses a preestablished CCl4-induced micronodular cirrhosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats

“…In this regard, it has been recently reported that the hepatocyte growth factor (HGF) stimulating hepatic collagenase activity partially prevented the onset and progression of liver fibrosis. 11 In addition, transfection with the human HGF gene to cirrhotic rats inhibited fibrogenesis and promoted complete resolution of fibrosis/cirrhosis. 12 Although the nature of the antifibrotic action of the HGF was not fully clarified, these data demonstrated the feasibility of reversing an established experimental cirrhosis in rats.…”

Portal branch ligation with a continuous hepatocyte growth factor supply makes extensive hepatectomy possible in cirrhotic rats

“…Moreover, HGF prevents and improves rat experimental hepatic fibrosis/cirrhosis. 21,22 We recently made a first report that a perioperative continuous HGF supply from the spleen effectively prevented postoperative liver failure following the 30% resection of cirrhotic livers in rats, 23 a promising result that we are attempting to expand.We speculated that preoperative PBL combined with a continuous HGF supply could accelerate the hypertrophy of the unoccluded lobes even in cirrhotic liver. In the present study, we examined the usefulness of this technique by assessing the degree of the compensatory hypertrophy and liver function following extensive hepatectomy in cirrhotic rats.…”

“…Moreover, HGF prevents and improves rat experimental hepatic fibrosis/cirrhosis. 21,22 We recently made a first report that a perioperative continuous HGF supply from the spleen effectively prevented postoperative liver failure following the 30% resection of cirrhotic livers in rats, 23 a promising result that we are attempting to expand.…”