Radiation hepatology of the rat: association of the production of prostacyclin with radiation-induced hepatic fibrosis.

The hypothesis that hepatic fibrosis is preceded by inflammation and formation of prostanoids from arachidonic acid liberated from damaged cell membranes was investigated. Liver slices were prepared using a Krumdieck precision tissue slicer from sham-irradiated rats or from rats whose livers had been irradiated with 25 Gy 137Cs gamma rays in which injury was allowed to develop in vivo for 6 to 55 days. Unused portions of the liver were analyzed for hydroxyproline content to determine hepatic fibrosis. A unique organ culture system was used to incubate liver slices for 2 h. Secretion into the incubation medium of aspartate aminotransferase and 6-keto prostaglandin F1 alpha were measured to quantify damage to the hepatocyte membrane and production of prostacyclin, respectively. A threefold increase in the concentration of 6-keto prostaglandin F1 alpha in the medium was evident by 13 days after irradiation. This elevated concentration of 6-keto prostaglandin F1 alpha persisted for the remainder of the study and preceded fibrosis, as measured by liver hydroxyproline concentration, and hepatocyte membrane damage, as measured by release of aspartate aminotransferase into the incubation medium or plasma. We therefore suggest that, in the non-generating liver, damage and breakdown of nonparenchymal liver cell membrane is the principal source of 6-keto prostaglandin F1 alpha. These results are also compatible with the supposition that inflammation and release of arachidonic acid metabolites are one of the early biochemical events leading to hepatic fibrosis. How the release of arachidonic acid metabolites might initiate and sustain radiation-induced fibrosis is discussed. An explanation for the difference in liver fibrosis induced by chemicals and radiation is also presented.