PREVENTIVE EFFECT OF HEPATOCYTE GROWTH FACTOR ON ACUTE SIDE EFFECTS OF CYCLOSPORIN A IN MICE

Cyclosporin A (CsA) is a potent, widely-prescribed immunosuppressant which has serious side effects. When recombinant human hepatocyte growth factor (rh-HGF) was co-administrated with CsA to mice, the severe digestive and/or neurological symptoms and degenerative changes in renal tubular cells and hepatocytes seen with cases of CsA administration were remarkably attenuated and mortality linked to CsA-administration was prevented by rh-HGF. HGF-administration stimulated the DNA synthesis of hepatocytes and renal tubular cells and facilitated reconstruction of hepato-renal tissue structure in vivo. Induction of HGF mRNA expression in the liver and kidney in CsA-administered mice was suppressed in the early stage of organ injury, while HGF mRNA levels increased in the lung three days after CsA-treatment. These observations suggest that the biological action of endogenous HGF is partly impaired after CsA-induced organ injury. Importantly, HGF had no apparent effect on the CsA-induced suppression of interleukin-2 mRNA expression in vitro, thereby indicating that the immunosuppressivc potential of CsA was not affected by HGF. Whether or not HGF will prove to have such positive effects in patients requiring CsA-treatment is the subject of ongoing study.