Abstract
Hepatocyte growth factor (HGF) is an endogenously expressed bioactive substance that has a strong anti-apoptotic effect. In this study, we biochemically and histologically characterized the effects of rh-HGF on in vitro human hepatocyte injury and mouse acute liver failure (ALF) models, both of which were induced by antibody-mediated Fas signaling. rh-HGF inhibited intracellular caspase-3/7 activation and cytokeratin 18 (CK-18) fragment release in both models. Histologically, rh-HGF dramatically suppressed parenchymal damage and intrahepatic hemorrhage. Among the laboratory parameters, prothrombin time (PT) was strongly preserved by rh-HGF, and PT was well correlated with the degree of intrahepatic hemorrhage. These results showed that the anti-apoptotic effect of rh-HGF on hepatocytes coincided strikingly with the suppression of intrahepatic hemorrhage. PT was considered to be the best parameter that correlated with the intrahepatic hemorrhages associated with hepatocellular damage. The action of rh-HGF might derive not only from its anti-apoptosis effects on liver parenchymal cells but also from its stabilization of structural and vasculature integrity.
Highlights
Human hepatocyte growth factor (HGF) is an endogenously expressed bioactive substance that was originally discovered in the serum of fulminant hepatitis patients because of its powerful ability to induce hepatocyte proliferation; it was originally recognized as a hepatocyte growth factor [1,2,3]
Cell apoptosis coincided with the increase of cytokeratin 18 (CK-18) M30 fragment concentration in the supernatant that resulted from its release from injured cells (Figure 1B)
Intracellular caspase-3/7 activity was suppressed by recombinant human HGF (rh-HGF) in a dose-dependent manner, and the mean of the half-maximal inhibitory concentration (IC50) value of three batches was calculated as 0.82 ng/mL
Summary
Human hepatocyte growth factor (HGF) is an endogenously expressed bioactive substance that was originally discovered in the serum of fulminant hepatitis patients because of its powerful ability to induce hepatocyte proliferation; it was originally recognized as a hepatocyte growth factor [1,2,3]. HGF has been found to induce strong and rapid anti-apoptotic effects against liver injury in mice [4,5]. These characteristics suggest the clinical utility of HGF for treating acute liver injury, such as acute liver failure (ALF). The immediate initiation of intensive medical support is required, but liver transplantation is the only treatment that considerably improves prognosis [8]. Prothrombin time (PT) is one of the key parameters for predicting patient prognosis, and the restoration of a prolonged PT-international normalized ratio (INR) to below 1.3 predicts an increased survival rate with conservative treatments [9]
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