Beneficial effect of Cyclosporin A on acute hepatic injury induced by galactosamine and lipopolysaccharide in rats.
Cyclosporin A (CsA), a potent immunosuppressive agent, is used clinically to prevent allograft rejection after organ transplantation. Although recent experimental studies show that CsA prevents severe hepatic injury associated with tumor necrosis factor-alpha (TNF-alpha), the efficacy of CsA has not been confirmed. In the present study, we evaluated whether CsA protects against the severe hepatic injury induced by simultaneous administration of D-galactosamine (GaIN, 200 mg/kg) and lipopolysaccharide (LPS, 10 µg/kg) into the portal vein. The method of CsA (10 mg/kg) was divided into four groups; i.e. preinjection (24 and 2 h before administration of GaIN and LPS), concomitant single-injection, multiple-interval injection (0, 3, 6, 9 and 15 h after administration of GaIN and LPS) and no treatment. In the group receiving multiple-interval injections of CsA, liver function parameters (total bilirubin, asparate aminotransferase and alanine aminotransferase levels in sera) were significantly improved and the development of massive hepatic necrosis was significantly prevented, but no improvement of liver function parameters or histological changes was shown either the pre- or concomitant single-injection groups. The serum levels of TNF-alpha and interferon-gamma showed no differences between the no treatment and multiple-interval injection groups. However, the serum level of interleukin 8 and neutrophil infiltration into the liver tissue after 24 h GaIN and LPS administration were significantly lower than those of the control group. The apoptotic index of liver tissue using the TUNEL method was not significantly different. Our data suggest that CsA protects against acute hepatic injury, if it is administered at the appropriate time during the course of hepatic injury.
Kawakami
T
First Department of Internal Medicine, School of Medicine, Iwate Medical University, Uchimaru 19-1, 020-8505, Morioka, Japan
Sato
S
Suzuki
K