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SUMMARY Liver damage was induced in rats by injection of dimethylnitrosamine (DMN) or carbon tetrachloride (CC4). Fibrin clots were observed in the hepatic sinusoids at 12 hours and soluble fibrin monomer complexes were markedly detected at 24 hours only in the rats given DMN. When antithrombin III concentrate was infused at 12 hours there was a dose dependent improvement of the values of serum total bilirubin, SGPT, prothrombin time, peripheral platelet count, and plasma fibrinogen and coagulation factor VIIIC and of the histological degree of liver injury at 24 hours in the DMN group. The CCl4-group showed no such improvement. Intravascular coagulation may complicate the course of certain types of acute liver injury and contribute to its aggravation in rats. Under such circumstances, treatment with antithrombin III concentrate would be beneficial.Both the sinusoidal deposition of fibrin and the increased catabolism of fibrinogen in acute liver failure suggest that intravascular coagulation may contribute to the cell injury in this condition.'`7 The efficacy of early treatment of such intravascular coagulation is, however, still unproven.2`7 It is not clear whether all types of acute liver failure are accompanied by intravascular coagulation and whether in any specific case it contributes to the aggravation of liver damage.Fibrinogen is converted into fibrin by thrombin. Thrombin activity can be inhibited by various plasma inhibitors.' Of the well known three protease

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Transforming growth factor alpha (TGFalpha) and hepatocyte growth factor (HGF) are mitogens for hepatocytes in vitro and in vivo, produced by hepatocytes or nonparenchymal cells such as stellate cells in the liver. It is still uncertain whether TGFalpha and HGF are essential for liver regeneration. To assess the role of these growth factors in liver regeneration, their circulating and hepatic levels were studied in various rat models of liver regeneration. Hepatic and plasma HGF levels were increased with increased number of mitotic hepatocytes in rats after partial hepatectomy or carbon tetrachloride intoxication. However, hepatic HGF levels were decreased despite an increased number of mitotic hepatocytes and increased or unchanged plasma HGF levels in rats given phenobarbital and in rats after dimethylnitrosamine intoxication, which can induce hepatic necrosis after apoptosis of hepatic stellate cells. In contrast, hepatic and serum TGFalpha levels were increased in all of the models. In sham-operated rats with no increased number of mitotic hepatocytes, hepatic and circulating levels of HGF were increased, whereas those levels of TGFalpha were unchanged. The results indicate that TGFalpha levels in liver and blood more closely correlate with hepatocyte mitogenesis than HGF levels.

Sphingosine 1-phosphate (S-1-P), a lipid mediator shown to be a ligand for aortic G protein-coupled receptor [corrected] (AGRs), endothelial differentiation gene (EDG)1, EDG3, and AGR16/EDG5, is stored in platelets and released on their activation. Platelet consumption occurs in acute liver injury. Hepatic stellate cells (HSCs) play an important role in wound healing. Effects of S-1-P on HSCs were investigated. S-1-P enhanced proliferation of culture-activated HSCs. The mitogenic effect was pertussis toxin sensitive, mitogen-activated protein kinase dependent, and more prominent at lower cell density. S-1-P increased contraction of collagen lattices containing HSCs, irrespective of activation state, in a C3 exotoxin-sensitive manner. mRNAs of EDG1 and AGR16, but not of EDG3, were detected in HSCs. In HSC activation, EDG1 mRNA levels were downregulated, whereas AGR16 mRNA levels were unchanged. Considering that HSCs are capable of production of extracellular matrices and modulation of blood flow in sinusoids, our results suggest that S-1-P may play a role in wound healing process in the liver.