leukotriene-c4 and Necrosis

Liver cell death by apoptosis and necrosis occurs upon the liver injury. Lipoxygenase pathway of arachidonic acid metabolism is known to regulate the viability and apoptosis in some cell types, but its role in hepatocyte cell death is not fully understood. We studied the influence of leukotrienes (LT) and lipoxygenase inhibitors on apoptosis and necrosis in rat hepatocyte primary culture by double staining with Hoechst 33342 and propidium iodide and electron microscopy. Treatment with general lipoxygenase inhibitor nordihydoguaiaretic acid and 5-lipoxygenase inhibitor caffeic acid (2. 10(-5) M) for 4 and 24 h induced hepatocyte apoptosis. LTB4 and LTC4 (10(-8) M) decreased the number of living cells and increased the number of necrotic cells. LTs exerted the same necrotic effect on hepatocytes, treated with lipoxygenase inhibitors. It is important that LTs decreased apoptosis induced by inhibitors treatment. These data suggest that lipoxygenase pathway of arachidonic acid metabolism is important regulator of hepatocytes viability and apoptosis The increase of lipoxygenase product formation, in particular LTs, may diminish apoptosis and increase necrosis in hepatocytes upon the liver injury.

Topics: Animals; Apoptosis; Cells, Cultured; Hepatocytes; Leukotriene B4; Leukotriene C4; Leukotrienes; Lipoxygenase Inhibitors; Male; Masoprocol; Necrosis; Rats; Rats, Wistar

The correlation between mucosal generation of nitric oxide (NO) and prostaglandin E2 (PGE2) in gastric adaptive cytoprotection was investigated.. Male Sprague-Dawley rats were pretreated with either N(w)-nitro-L-arginine methyl ester (L-NAME, 12.5 mg/kg i.v.) or indomethacin (5 mg/kg s.c.). Following that, mild irritant 20% ethanol was administered, 15 min prior to 100% ethanol challenge.. Macroscopic gastric mucosal damage, NO synthase activity, mucosal PGE2 and leukotriene C4 (LTC4) levels were measured.. Administration of L-NAME and indomethacin significantly reduced the protective action of 20% ethanol against 100% ethanol-induced gastric mucosal damage. Besides, mucosal activity of constitutive NO (cNO) synthase, but not of the inducible isozyme (iNO synthase), was elevated following 20% ethanol treatment. This was accompanied by a reduction in mucosal leukotriene C4 level. Indomethacin significantly inhibited mucosal PGE2 biosynthesis but increased cNO synthase activity. Nevertheless, L-NAME reduced both cNO and iNO formation and prevented the increase in cNO formation caused by 20% ethanol, while enhancing mucosal PGE2 production. Combined L-NAME and indomethacin treatment markedly potentiated ethanol-induced mucosal damage, and completely prevented the increase in cNO or PGE2 biosynthesis when either compound was given alone.. These findings suggest a co-regulatory relationship between mucosal NO and PG in the gastric defense system, which will be released after activation by the mild irritants to induce cytoprotection.

Topics: Animals; Cyclooxygenase Inhibitors; Dinoprostone; Enzyme Inhibitors; Ethanol; Gastric Mucosa; Gastritis; Indomethacin; Leukotriene C4; Male; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley

In order to elucidate the relation between tissue eicosanoids and liver injury due to bile duct obstruction, we have examined the effects of iloprost, a stable analogue of prostaglandin I2 (PGI2), and UK 38485 (UK), an inhibitor of thromboxane synthetase, on prostaglandin E2 (PGE2) and leukotriene C4(LTC4) in guinea pig liver. 56 male guinea pigs were divided into the following groups: (i) sham operations (SHAM), (ii) bile duct ligated (BDL) group, (iii) guinea pigs given UK (5 micrograms/kg body wt intraperitoneally 10 min, 8 h and 16 h after bile duct ligation), and (iv) guinea pigs treated with iloprost (ILO) (2 micrograms/kg body wt intraperitoneally 10 min, 8 h and 16 h after bile duct ligation). Liver damage was assessed by blind quantitation of liver cell necrosis. Bile duct ligation caused an increase in tissue PGE2-like activity and a decrease LTC4-like activity. But the most pronounced elevation of PGE2-like activity was observed in ILO treated group. The LTC4-like activity level improved significantly in the UK-treated BDL group compared with the BDL only and ILO treated animals. Also, UK was found to be beneficial in preventing the liver cell necrosis due to cholestasis. It is concluded that the ratio of PGE2/LTC4 in liver is a valuable marker for cholestatic injury.

Topics: Animals; Bile Ducts; Biomarkers; Cholestasis, Extrahepatic; Dinoprostone; Guinea Pigs; Iloprost; Imidazoles; Leukotriene C4; Ligation; Liver; Male; Necrosis; Thromboxane-A Synthase

5-Lipoxygenase (5-LO) converts arachidonic acid, released from membrane phospholipids upon external stimulation, to leukotriene C4 (LTC4), which induces various kinds of cellular and molecular responses. We examined the effects of 5 min of ischemia on brain 5-LO and LTC4 during reperfusion using the gerbil model of transient forebrain ischemia that develops neuronal necrosis selectively in the hippocampus. Neurons exhibited dense 5-LO immunoreactivity; 5-LO was partially redistributed from cytosolic to particulate fractions 3 min during reperfusion. LTC4 was generated in neurons and was increased in all forebrain regions during reperfusion. Postischemic increases in LTC4 were inhomogeneous; a greater increase was observed in the hippocampus (13.37 +/- 0.24 pmol/g tissue) than in the other regions (cerebral cortex: 3.29 +/- 1.09 pmol/g). Superoxide dismutase and dimethylthiourea, oxygen radical scavengers, attenuated the production of LTC4 and damage to the neurons in the hippocampus during reperfusion. Our findings indicated that reperfusion, which was associated with translocation of cytosolic 5-LO to membranes and generation of oxygen radicals, induced the production of LTC4 and suggested that excess LTC4 production may mediate irreversible reperfusion injuries in the hippocampal neurons.

Topics: Animals; Arachidonate 5-Lipoxygenase; Brain Ischemia; Cerebral Cortex; Gerbillinae; Hippocampus; Humans; Immunohistochemistry; Leukotriene C4; Male; Necrosis; Neurons; Recombinant Proteins; Reperfusion Injury; Superoxide Dismutase; Thiourea; Tissue Distribution