EVIDENCE FOR THE PRESENCE OF AN INACTIVE PRECURSOR OF HUMAN HEPATOCYTE GROWTH-FACTOR IN PLASMA AND SERA OF PATIENTS WITH LIVER-DISEASES

Human hepatocyte growth factor (hHGF), which is now known to be the sa me protein as the scatter factor and the tumor cytotoxic factor, is a heterodimeric protein with one heavy chain and one light chain linked together by a disulfide bond, and is thought to be involved in liver r egeneration. Using an enzyme-linked inmunosorbent assay (ELISA) and We stern blot analysis, we found that a significant amount of single chai n precursor of hHGF (pro-hHGF) was present in plasma of patients with fulminant hepatic failure (FHF) and that normal human serum contained a protease or proteases that convert pro-hHGF to a heterodimeric (matu re) form of hHGF. We also showed that the processing protease activity for hHGF was suppressed by such serine protease inhibitors as leupept in, antipain, and aprotinin, and that sera of patients with liver dise ases such as fulminant hepatic failure, acute hepatitis, chronic hepat itis, and cirrhosis contained not only pro-hHGF but also the protease, This is the first report showing the presence of pro-hHGF in human bl ood, and our observations suggest that hHGF is synthesized and secrete d from the hHGF-producing cells as an inactive pro-hHGF after hepatic injuries, and the pro-hHGF is then converted to an active heterodimeri c form of hHGF in the blood. It is also suggested that plasma of patie nts with liver diseases contains an active protease or proteases that convert pro-hHGF to a mature form of hHGF.