Histochemical and biochemical studies on the effect of the prostacyclin derivative iloprost on CCI4-induced lipid peroxidation in rat liver and its significance for hepatoprotection

Abstract

In the present study, it was investigated whether the prostacyclin derivative Iloprost would protect hepatocytes against CCl 4 -induced liver injury and which mechanism(s) of hepatocellular pathogenesis might be affected by it. Rats were treated with a single oral dose of CC14 (2 ml per kg); Iloprost was infused continuously from 2 to 4 hr before intoxication until killing. The following results were obtained. The CCl 4 -induced release of AST, lactate dehydrogenase and alkaline phosphatase into the serum was reduced by 50 to 70% in rats treated with doses of 0.1 and 0.5 μg Iloprost per kg per min. Infusion of 0.02 and 0.004 μg Iloprost per kg per min did not affect the CCl 4 -induced enzyme release into the blood. CCl 4 induced the occurrence of aldehydes (products of lipid peroxidation), which were detected by histochemical and biochemical means. At 12, 48 and 72 hr after CCI 4 , the aldehyde-positive liver section area was about 58, 69 and 16% in rats treated with CCl 4 alone, but only about 18, 13 and <1% in rats treated additionally with Iloprost. The aldehyde-positive hepatocytes were located predominantly in the centrilobular zone of the liver. At 24 hr the extent of the aldehyde-positive section area was the same in rats with or -without Iloprost treatment (about 90%). Biochemical determination, however, revealed that at this time point the malondialdehyde content after Iloprost in rats was about 70% lower than without Iloprost treatment. Other histochemical and histological signs of cell damage were also reduced by Iloprost treatment, predominantly in the periportal zone: loss of granular pyroninophilia indicating destruction of ribosomal RNA, fatty degeneration and hepatocellular necrosis visible in hematoxylin and eosin-stained sections. At 48 and 72 hr after CCI 4 , the mitotic activity in the liver of rats treated with Iloprost was about one-half and one-quarter of that without Iloprost treatment. In conclusion, Iloprost partially protects hepatocytes against CCI 4 -induced cell damage and death; periportal hepatocytes appear to be protected more effectively than centrilobular hepatocytes. The reduced content of lipid peroxidation products indicates that reduction of lipid peroxidation and/or stimulation of aldehyde elimination (repair) is involved in the hepatoprotective action of Iloprost.