The role of leukotrienes was investigated in frog virus 3-induced hepatitis in rats. Frog virus 3 elicited an enhanced generation of cysteinyl leukotrienes in vivo as monitored by measurement of N-acetyl-leukotriene E4 as the major endogenous metabolite of cysteinyl leukotrienes secreted into rat bile. N-Acetyl-leukotriene E4 concentrations were elevated for more than 4 hr after frog virus 3 injection. In vitro experiments using cultured rat liver Kupffer cells of high purity indicated that these cells can produce and metabolize leukotrienes and are thus a possible source of leukotrienes elicited in vivo by frog virus 3. The selective 5-lipoxygenase inhibitor AA 861 and the dual inhibitor of arachidonate lipoxygenase and cyclooxygenase, BW 755C, reduced the hepatocellular injury after a high dose of frog virus 3 by about 50 and 80%, respectively, as judged from plasma activities of ALT and sorbitol dehydrogenase at 24 hr after frog virus 3 administration. Our in vivo and in vitro studies argue in favor of an important role of leukotrienes as mediators in frog virus 3 hepatitis in rats.
The biological potential of leukotrienes comprises effects on smooth muscle tone, vascular permeability and infiltration of inflammatory cells (1-8). An important role for these mediators of the eicosanoid family has been demonstrated so far in disease processes such as bronchial asthma (1, 4-6), tissue trauma (9) and shock (6, 8, 10-12) but also in local inflammation (5, 6, 13-16) and acute liver injury (17).
Acute hepatitis is observed in the lethal action of frog virus 3 (FV3) in mice and rats . Early actions of FV3 are targeted on Kupffer and endothelial cells of the liver (18). This hepatotropic virus (18) exerts its toxic effects due to structural viral proteins (20) which kill the animals within about 30 hr.
The aim of this study was to examine the possible involvement of leukotrienes in the pathogenesis of FV3induced hepatitis in rats by the use of inhibitors and by leukotriene measurements in uiuo and in hepatic cells in