leukotriene-b4 and Liver-Diseases

Leukotrienes (LT), composed of cysteinyl LT (cLT; LTC(4), LTD(4), and LTE(4)) and LTB(4), are potent lipid mediators enhancing the vascular permeability and recruitment of neutrophils, which are common features of hepatic ischemia/reperfusion (I/R) injury. The aim of this study was to investigate whether LT can mediate the liver and lung injuries following hepatic I/R.. Sprague-Dawley rats were subjected to 90 min of partial hepatic ischemia followed by 3, 12, and 24 h of reperfusion. In the hepatic and pulmonary tissues, LT content and the mRNA expression of LT-synthesis enzymes, 5-lypoxygenase (5-LO), LTC(4) synthase (LTC(4)-S), and LTA(4) hydrolase (LTA(4)-H) were measured. Tissue injuries were assessed by plasma ALT, histological examination, and wet-to-dry tissue weight ratios.. The cLT content in the hepatic tissue after 12 and 24 h reperfusion was increased 4- to 5-fold compared to controls and this was accompanied by the enhancement of hepatic edema and plasma ALT elevation. There were no significant changes in the mRNA expression of LT-synthesis enzymes in both tissues. LTB(4) levels were not increased despite a significant neutrophil infiltration in both tissues.. These data suggest that cLT are generated in the liver during the reperfusion period and may contribute to the development of hepatic edema and exert cytotoxicity. Factors other than LTB(4) may contribute to neutrophil infiltration.

Topics: Alanine Transaminase; Animals; Arachidonate 5-Lipoxygenase; Cysteine; Edema; Epoxide Hydrolases; Glutathione Transferase; Leukotriene B4; Leukotrienes; Liver; Liver Circulation; Liver Diseases; Lung; Male; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger

We investigated the pathogenesis of septic liver injury in rats caused by cecal ligation and puncture. In this model, numerous neutrophils accumulated in the liver in parallel with the development of liver dysfunction. The supernatants of hepatic macrophages isolated from these septic rats 24 hr after cecal ligation and puncture had enhanced chemotactic activities for human neutrophils. These results suggest that in sepsis, hepatic macrophages attract neutrophils to the liver. Human neutrophils preincubated in this macrophage supernatant had the following biological activities not seen in the sham-operated controls. (a) They became more adherent to cultured endothelial cells through up-regulation of adhesion molecules such as CD11b/CD18, (b) their chemiluminescence was markedly elevated. These functional changes of cecal ligation and puncture hepatic macrophages were the same as those in endotoxin-pretreated hepatic macrophages after isolation from normal rats. Therefore we suspect that hepatic macrophages are activated by portal vein endotoxin in sepsis. These activated hepatic macrophages secreted chemical mediators of inflammation, including leukotriene B4 and tumor necrosis factor. In conclusion, hepatic macrophages seem to interact closely with neutrophils and play an important role in the pathogenesis of septic liver injury.

Topics: Animals; Antigens, CD; Arteries; CD11 Antigens; CD18 Antigens; Cell Adhesion; Chemotaxis, Leukocyte; Endothelium, Vascular; Endotoxins; Leukotriene B4; Liver; Liver Diseases; Macrophages; Male; Neutrophils; Portal Vein; Rats; Rats, Wistar; Sepsis; Tumor Necrosis Factor-alpha

Arachidonate metabolism was examined in rats with experimentally induced acute and chronic liver injuries. Acute liver injury was induced by a single administration of D-galactosamine (D-Galn) and lipopolysaccharide (LPS) or carbon tetrachloride (CCl4). Chronic liver injury was produced by several administrations of CCl4 for 5 weeks. Non-parenchymal liver cells from rats with D-Galn/LPS-induced acute liver injury produced prominently leukotriene B4 and 5-hydroxy-arachidonic acid which were hardly synthesized by the normal rat liver. No apparent changes were observed in the arachidonate metabolism of the non-parenchymal cells of the acute CCl4-injured liver. In chronic liver injury, the production of 6-ketoprostaglandin F1 alpha, a stable metabolite of prostaglandin I2, by the non-parenchymal cell fraction was significantly enhanced in contrast with the fixed amount of the other arachidonate metabolites. These results suggested the arachidonate metabolism by non-parenchymal liver cells might change according to the pathogenesis of the liver disease.

Topics: Acute Disease; Animals; Arachidonic Acids; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Chronic Disease; Eicosanoids; Galactosamine; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipopolysaccharides; Liver; Liver Cirrhosis, Experimental; Liver Diseases; Male; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Rats, Wistar

Topics: Animals; Leukocytes, Mononuclear; Leukotriene B4; Liver; Liver Diseases; Rats

A study was conducted to investigate production rate of leukotriene B4 (LTB4) in parenchymal and sinusoidal liver cells of rats with acute hepatic failure (AHF). AHF was induced by simultaneous administration of D-galactosamine (GalN) and endotoxin (LPS), and parenchymal as well as sinusoidal liver cells were isolated by collagenase perfusion method. Following preincubation for 15 min, isolated cellular fractions were incubated with Ca-ionophore (2 microM) for 5 min, and levels of LTB4 in culture media before and 5 min after addition of Ca-ionophore were analyzed by HPLC. Following results were obtained: The production rate of LTB4 was found to be the highest in Kupffer cells (7.2ng/10(6) cells/5 min), followed by endothelial cells (1.1), stellate cells (0.2) and parenchymal cells (not detectable). The production rate of LTB4 in both Kupffer cells and endothelial cells was found to reach a maximum in the fraction isolated 60 min after administration of GalN and LPS. Treatment with AA861, one of the selective inhibitors of 5-lipoxygenase, was shown to reduce the production of LTB4 in Kupffer cells to 53% at 10(-7)M and above 99% at higher than 10(-5)M. In conclusion, the majority of LTB4 generated in the liver of rats with AHF was found to be synthesized in Kupffer cells and, to a lesser extent, in endothelial cells, and the enhanced production of LTB4 was found to be greatly inhibited by treatment with AA861.

Topics: Acute Disease; Animals; Chemical and Drug Induced Liver Injury; Endotoxins; Galactosamine; Leukotriene B4; Lipopolysaccharides; Liver; Liver Diseases; Male; Rats; Salmonella enteritidis

Topics: Humans; Leukotriene B4; Liver Diseases; Neutrophils; SRS-A