Role of leukotriene B4 in the pathogenesis of hepatic ischemia-reperfusion injury in the rat.
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 aminotransferase (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.(ABSTRACT TRUNCATED AT 250 WORDS)
Hughes
H
H
Department of Medicine, Baylor College of Medicine, Houston, Texas.
Farhood
A
A
Jaeschke
H
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D007211:Indoles / Q000494:pharmacology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D008099:Liver / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002722:Chlorobenzenes
D000410:Alanine Transaminase; D007211:Indoles; D007975:Leukotriene B4; C060893:MK-886; D002722:Chlorobenzenes