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Abstract

In the present study, it was investigated whether the prostacyclin derivative Iloprost would protect hepatocytes against CCl4-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 CCl4-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 CCl4-induced enzyme release into the blood.

CCl4 induced the occurrence of aldehydes (products of lipid peroxidation), which were detected by histochemical and biochemical means. At 12, 48 and 72 hr after CCI4, the aldehyde-positive liver section area was about 58, 69 and 16% in rats treated with CCl4 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 CCI4, 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 CCI4-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.