Preventive effect of cyclosporin A on experimentally induced acute liver injury in rats.
We examined the effect of cyclosporin A (CsA) on the pathogenesis of acute experimental liver injury in rats induced by injection of heat-killed Propionibacterium acnes (P. acnes) and subsequent injection of lipopolysaccharide (LPS). Pretreatment with CsA significantly reduced serum alanine aminotransferase (ALT), serum tumor necrosis factor-alpha (TNF-alpha) production, without changing the TNF-alpha mRNA level in the liver, and plasma interferon-gamma (IFN-gamma), following LPS injection in this model. Twenty-four-hour mortality was also markedly improved, from 100% in the P. acnes plus LPS group to 0% in the CsA-pretreated group. Although direct addition of CsA to isolated hepatic macrophages from P. acnes-pretreated rats did not prevent the production of TNF-alpha and active oxygen species, isolated hepatic macrophages from P. acnes plus CsA-pretreated rats significantly reduced their production in response to the addition of LPS. These results suggest that CsA protects against P. acnes plus LPS-induced acute liver injury, not by direct inhibition of hepatic macrophage activation, but by indirect prevention of hepatic macrophage activation, presumably related to the reduction in plasma IFN-gamma levels.
Wasaki
S
S
Department of Internal Medicine, Yamaguchi University, School of Medicine, Yamaguchi-Prefecture, Japan.
Sakaida
I
I
Uchida
K
K
Kimura
T
T
Kayano
K
K
Okita
K
K
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000382:microbiology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D011425:Propionibacterium acnes; D051381:Rats; D017208:Rats, Wistar
D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016572:Cyclosporine