Role of leukotriene B4 in the pathogenesis of hepatic ischemia-reperfusion injury in the rat

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Journal Article

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Prostaglandins, Leukotrienes and Essential Fatty Acids








A common feature to most models of ischemia-reperfusion injury is the accumulation of polymorphonuclear leukocytes (PMNs) into the post-ischemic tissue during the reperfusion period. Interventions that lead to decreased PMN infiltration protect against tissue injury and therefore a knowledge of the chemotactic mediators leading to PMN accumulation is essential to understanding the pathogenesis of the injury and to the development of successful therapeutic strategies. Leukotriene B4 (LTB4), a metabolite formed via the 5-lipoxygenase pathway from arachidonic acid, is one of the most potent chemotactic mediators known. We have investigated the formation of LTB4 in a well characterized model of hepatic ischemia-reperfusion injury in the rat and made use of a specific leukotriene biosynthesis inhibitor, L663,536, to determine the importance of LTB4 in the pathogenesis of the injury. LTB4 concentrations were measured with a specific and sensitive gas chromatographic-mass spectrometric method previously developed in our laboratory. In liver tissue LTB4 levels were below the detection limit of 20 pg/g before 45 min ischemia and did not increase during the first 6 h of reperfusion. However, at 15 h and 24 h reperfusion LTB4 concentrations had increased to levels 50-fold those in control liver (867 ± 267 pg/g). The increase of plasma alanine amminotransferase (ALT) activities indicated two phases of injury, an initial phase during the first few hours of reperfusion, and a second more severe injury phase between 6 h and 24 h reperfusion. PMNs accumulated in tissue throughout the reflow period reaching 700 ± 49 per 50 high power fields (HPF) at 24 h. Treatment with L663,536 inhibited LTB4 formation by 90% in 24 h post-ischemic liver but had no effect on liver injury, as indicated by plasma ALT activities and liver necrosis. Inhibition of LTB4 biosynthesis also had no effect on PMN accumulation in the liver (782 ± 28 per 50 HPF). These results support the conclusion that LTB4 is not a chemotactic mediator in this rat model and appears to play no relevant role in the pathogenesis of the injury. © 1992.

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