0-7400 Tiibingen, Federal Republic of Germany
Responses of isolated perfused rat liver to leukotriene C4 were studied in order to assess the mechanisms involved in leukotriene-mediated liver injury. Infusion of leukotriene C4 (11 and 44 pmoles per min per gm liver weight) into the portal vein resulted in a rise in portal pressure, a decrease in oxygen consumption, an increase in hepatic glucose and lactate efflux and lactate/pyruvate ratio in the perfusate and a small decrease in bile flow. Isoproterenol (1 @) counteracted the effects of leukotriene C4 on respiration and portal pressure, whereas bile flow and glucose efflux were reversibly stimulated. The same changes were observed upon withdrawal of leukotriene C4. The release of glucose was correlated with the increase in oxygen consumption upon both isoproterenol addition and withdrawal of leukotriene C4. These results are indicative of leukotriene C4-induced microcirculatory redistribution of perfusate flow. Since, in the presence of nitroprusside (50 a), both the effects of leukotriene C4 and their reversal by isoproterenol were diminished, a vascular site of action can be assumed. Accordingly, the accompanying metabolic responses can be explained by gradual changes in oxygen supply to parts of the liver. Reversibility of the leukotriene Cq effects and lack of short-term impairment of viability of the isolated liver suggest that leukotriene-mediated liver injury is a long-term effect related to events subsequent to microcirculatory changes.
Peptide leukotrienes are arachidonic acid metabolites of the 5-lipoxygenase pathway (1) which have been identified as potent mediators of liver injury (2). In particular, they have been demonstrated to be produced in endotoxin-mediated shock in rats (3, 4). Rodents can be sensitized to endotoxin by treatment with galactosamine (5), and it has recently been suggested that an ischemia/ reperfusion injury was involved in this model of hepatitis in mice (6).
Since leukotrienes C4 and D, are known to be potent vasoconstrictors in other organs (cf. [7][8][9], it can be hypothesized that oxygen deficiency and consequent liver injury may be induced by a direct vasoconstrictive effect of leukotrienes. In a first attempt to verify this hypoth-