leukotriene-b4 and Chemical-and-Drug-Induced-Liver-Injury

Over the last several years, information on methotrexate's mechanism(s) of action (which affects its efficacy) and toxicities continue to evolve. This popular second line agent (DMARD) is a potent anti-inflammatory drug, with effects on LTB4 and adenosine release (EC-50: 1-13 nM). As such, it may be a sufficiently potent anti-inflammatory drug to affect rheumatoid arthritis's basic course, as shown by a recent meta-analysis where methotrexate equalled gold and was better than azathioprine, when examining radiographic erosions. Its toxicities continue to be documented, with cirrhosis occurring between 2:100 and 1:1000 cases. Pneumonitis continues to be found. NSAID-MTX interactions, too, have been documented, although their kinetic mechanisms remain controversial.

Topics: Adenosine; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Drug Interactions; Humans; Leukotriene B4; Lung Diseases; Methotrexate

Dioxin and related chemicals alter the expression of a number of genes by activating the aryl hydrocarbon receptors (AHR) to produce a variety of disorders including hepatotoxicity. However, it remains largely unknown how these changes in gene expression are linked to toxicity. To address this issue, we initially examined the effect of 2,3,7,8-tetrachrolodibenzo-

Topics: Animals; Chemical and Drug Induced Liver Injury; Dioxins; Leukotriene B4; Neutrophil Activation; Neutrophil Infiltration; Neutrophils; Polychlorinated Dibenzodioxins; Rats; Rats, Mutant Strains; Receptors, Aryl Hydrocarbon; Receptors, Leukotriene B4

We previously confirmed that rats overloaded with aluminum exhibited hepatic function damage and increased susceptibility to hepatic inflammation. However, the mechanism of liver toxicity by chronic aluminum overload is poorly understood. In this study, we investigated changes in the 5-lipoxygenase (5-LO) signaling pathway and its effect on liver injury in aluminum-overloaded rats. A rat hepatic injury model of chronic aluminum injury was established via the intragastric administration of aluminum gluconate (Al(3+) 200mg/kg per day, 5days a week for 20weeks). The 5-LO inhibitor, caffeic acid (10 and 30mg/kg), was intragastrically administered 1h after aluminum administration. Hematoxylin and eosin staining was used to visualize pathological changes in rat liver tissue. A series of biochemical indicators were measured with biochemistry assay or ELISAs. Immunochemistry and RT-PCR methods were used to detect 5-LO protein and mRNA expression in the liver, respectively. Caffeic acid administration protected livers against histopathological injury, decreased plasma ALT, AST, and ALP levels, decreased TNF-α, IL-6, IL-1β and LTs levels, increased the reactive oxygen species content, and down-regulated the mRNA and protein expressions of 5-LO in aluminum overloaded rats. Our results indicate that 5-lipoxygenase activation is mechanistically involved in chronic hepatic injury in a rat model of chronic aluminum overload exposure and that the 5-LO signaling pathway, which associated with inflammation and oxidative stress, is a potential therapeutic target for chronic non-infection liver diseases.

Topics: Alanine Transaminase; Alkaline Phosphatase; Aluminum; Animals; Arachidonate 5-Lipoxygenase; Aspartate Aminotransferases; Caffeic Acids; Chemical and Drug Induced Liver Injury; Cytokines; Leukotriene B4; Leukotriene C4; Lipoxygenase Inhibitors; Liver; Male; Malondialdehyde; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger

Leukotrienes (LTs), metabolites of arachidonic acid through 5-lipoxygenase (5-LOX), have been known to play a role in leukocyte recruitment. However, the contribution of LTB4 to liver microcirculatory dysfunction during endotoxemia remains unknown. LTB4 receptor (BLT1) has been identified as a high-affinity receptor specific for LTB4. The present study was conducted to examine the roles of LTB4 and BLT1 in hepatic microcirculatory dysfunction elicited by LPS in mice. The number of leukocytes adhering to the endothelial cells of the hepatic microvessels and perfused sinusoids was determined 4 h after the administration of LPS (0.3 mg/kg, i.v.) to male C57Bl6 mice by in vivo microscopy. A 5-LOX synthase inhibitor, AA-861 (10 or 100 mg/kg, s.c.), was administered 30 min before LPS injection. BLT1 knockout mice were used to investigate whether LPS-induced hepatic microcirculatory dysfunction is mediated by BLT1 signaling. The expression of 5-LOX, intercellular adhesion molecule (ICAM) 1, and TNF-[alpha] in the liver was measured by real-time reverse-transcriptase-polymerase chain reaction. The administration of LPS caused significant accumulation of leukocyte adhesion to the hepatic microvessels and reduced sinusoidal perfusion when compared with saline-treated mice. The hepatic microcirculatory dysfunction elicited by LPS was minimized in mice pretreated with AA-861 or in BLT1 knockout mice. This was associated with the suppression of hepatic expression of 5-LOX, ICAM-1, and TNF-[alpha]. These findings suggest that the LTB4/BLT1 pathway mediates hepatic microcirculatory dysfunction by enhanced expression of ICAM-1 and TNF-[alpha] in a murine model of endotoxemia.

Topics: Animals; Chemical and Drug Induced Liver Injury; Intercellular Adhesion Molecule-1; Leukotriene B4; Lipopolysaccharides; Lipoxygenase Inhibitors; Liver; Male; Mice; Mice, Knockout; Microcirculation; Receptors, Leukotriene B4

The present study evaluated the role of endotoxin, prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and thromboxane B2 in alcoholic liver injury. Animals (4-5 per group per time period) were fed ethanol and either saturated fat (SE group) or corn oil (CE group) and sacrificed at various time intervals: 1, 2, and 4 weeks. Non parenchymal cells (NPC) were isolated and the spontaneous and LPS-stimulated production of eicosanoids was evaluated. In addition, severity of pathology, plasma levels of endotoxin, TXB2, LTB4 and PGE2 were compared in the two groups. The severity of fatty, liver, necrosis and inflammation was significantly greater in the CE group compared to the SE group after 1 month. Plasma endotoxin levels were significantly higher in the CE group vs. SE group at all time periods studied. PGE2 levels in NPCS and plasma were in general higher in the SE group. LTB4 levels in NPCS declined with time in the SE group; in contrast the levels rose in the CE group. There was no difference in LTB4 levels in plasma between the two groups. TXB2 levels in plasma and NPCS were significantly higher in the CE group at all times. The pattern of LPS-stimulated eicosanoid production by NPC in the two groups (SE and CE) suggested the development of endotoxin tolerance in the CE group. However, an additional modulatory effect of ethanol was also suggested by our findings.

Topics: Animals; Chemical and Drug Induced Liver Injury; Corn Oil; Dietary Fats; Dinoprostone; Drug Tolerance; Eicosanoids; Ethanol; Leukotriene B4; Lipopolysaccharides; Male; Rats; Rats, Wistar; Thromboxane B2

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

Oral pretreatment with E3330, a novel quinone derivative, attenuated liver injury induced with tumor necrosis factor-alpha in galactosamine-sensitized mice. Tumor necrosis factor-alpha is known to induce inflammatory mediators such as leukotrienes and prostanoids. An in vitro study showed that E3330 inhibited the generation of leukotriene B4 and thromboxane B2, but enhanced prostaglandin E2 generation from rat peritoneal exudate cells stimulated with the Ca(2+)-ionophore, A23187. These findings suggest that the protective effect of E3330 on galactosamine/tumor necrosis factor-alpha hepatitis is due at least in part to its inhibition of the generation of leukotrienes. The inhibition of thromboxane B2 generation or the enhancement of prostaglandin E2 generation by E3330 may also contribute to its hepatoprotective effect.

Topics: Animals; Ascitic Fluid; Benzoquinones; Chemical and Drug Induced Liver Injury; Dinoprostone; Galactosamine; In Vitro Techniques; Leukotriene B4; Male; Mice; Mice, Inbred C3H; Propionates; Rats; Thromboxane B2; Tumor Necrosis Factor-alpha

It has been reported that leukotrienes (LTs) may play a role in inflammatory liver diseases, and several inhibitors of LTs show an inhibitory effect on experimental liver injuries. In this study, the effect of Gomisin A (TJN-101), which is a lignan component of schisandra fruits, on the arachidonic acid cascade in macrophages was examined to explain the mechanisms of the inhibitory effect of TJN-101 on liver injuries. The production of leukotriene B4 was suppressed by treatment with TJN-101, while the activity of 5-lipoxygenase was not affected. The release of arachidonic acid from macrophages stimulated with fMet-Leu-Phe or the Ca++ ionophore A23187 was suppressed by treatment with TJN-101. The activity of phospholipase A2 was not affected by treatment with TJN-101. These results suggested that TJN-101 produces an inhibitory effect on the biosynthesis of LTs by preventing the release of arachidonic acid, and it was thought that the preventive effect on the arachidonic acid cascade may be partially associated with the inhibitory effect of TJN-101 on liver injuries.

Topics: Animals; Arachidonic Acids; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Exudates and Transudates; Leukotriene B4; Lignans; Lipoxygenase; Macrophages; Male; Phospholipases A; Phospholipases A2; Polycyclic Compounds; Rats; Rats, Inbred Strains

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