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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interaction between activated human polymorphonuclear leukocytes (PMNL) and endothelial regulation of isolated pig coronary artery tone was examined. PMNL were isolated from venous blood of healthy human volunteers. Pig coronary artery rings were incubated in an organ chamber, and isometric tension changes induced by opsonized zymosan (1 mg/ml)-activated PMNL were examined. Activated PMNL elicited dose-dependent contraction (maximum value 45.9 +/- 4.1% of precontraction, mean +/- SEM] in prostaglandin F2 alpha (PGF2 alpha)-precontracted rings. The contraction was markedly attenuated by superoxide dismutase (SOD 100 U/ml) to 9.9 +/- 2.4% (p < 0.001), but not by catalase (1,000 U/ml). After inhibition of basal production of endothelium-derived relaxing factor (EDRF) (nitric oxide, NO) by endothelial removal or by treatment of an inhibitor of NO synthase, NG-monomethyl-L-arginine (L-NMMA), PMNL also failed to induce the contraction. A 5-lipoxygenase inhibitor (AA-861) and a cyclooxygenase inhibitor (indomethacin) did not alter the contraction to activated PMNL significantly. Time course of oxygen free radical release from PMNL measured by luminol-dependent chemiluminescence was closely synchronized with that of the endothelium-dependent contraction elicited by PMNL. In each preparation of PMNL, the maximum luminescence count and the maximum contraction induced by activated PMNL showed significant positive correlation quantitatively (r = 0.958, p < 0.001). Activated human PMNL elicited endothelium-dependent contraction in isolated pig coronary arteries. The contraction may be mediated through inactivation of basal production of EDRF (NO) by superoxide anions released from PMNL.
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PMID:Activated human polymorphonuclear leukocytes elicit endothelium-dependent contraction in isolated pig coronary arteries. 768 46

We investigated the effects of bestatin, a prototype leukotriene A4 (LTA4) hydrolase inhibitor, on leukotriene (LT) formation and pulmonary artery perfusion pressure (Ppa) in isolated, perfused rat lungs. In lung parenchymal strips stimulated with a 10 microM concentration of the Ca2+ ionophore A23187, bestatin inhibited LTB4 formation with an IC50 = 10.4 +/- 30 microM (mean +/- SD, N = 4). It did not alter cysteinyl LT formation, confirming that it inhibited LTA4 hydrolase selectively, without inhibiting phospholipase, 5-lipoxygenase, or LTC4 synthase. In isolated, perfused lungs stimulated with 10 microM A23187, 300 microM bestatin inhibited LTB4 release by 72.2 +/- 10.6% (mean +/- SEM, N = 6, P < 0.01) but had no significant effect on LTE4 formation (P > 0.5). In these perfused lungs, bestatin did not alter the change in Ppa following stimulation with A23187. This effect is consistent with the insubstantial re-direction of LTA4 toward formation of vasospastic cysteinyl LTs. Separate experiments used lungs from rats treated with lipopolysaccharide endotoxin in vivo, prior to isolation, perfusion, and stimulation with 5 microM formyl-methionyl-leucyl-phenylalanine, in vitro. In these inflamed lungs, 750 microM bestatin inhibited LTB4 formation (P < 0.05) and increased LTE4 formation (P < 0.05), compatible with selective inhibited LTB4 hydrolase. The re-direction of LTA4 metabolism toward formation of cysteinyl LTs by inflamed, perfused lungs did not cause an increase in P(pa).
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PMID:Modulation of pulmonary leukotriene formation and perfusion pressure by bestatin, an inhibitor of leukotriene A4 hydrolase. 804 14

This study was performed to examine the immunosuppressive effect of a 5-lipoxygenase inhibitor, AA-861, on liver transplantation in rodents, and also to examine the production of eicosanoids during rejection of liver allograft in these animals. Rats were divided into three groups: group I (syngenic orthotopic liver transplantation from LEW to LEW), group II (allogenic OLT from ACI to LEW with dimethyl sulfoxide), and group III (allogenic OLT from ACI to LEW with AA-861 [20 mg/kg/day] s.c. dissolved in DMSO). Histological examinations were performed, survival time was monitored, and eicosanoid levels at 3, 5, and 7 days after transplantation were measured. Mean survival time in group III was significantly longer than that in group II (36.0 +/- 6.8 vs. 11.1 +/- 0.7 days, mean +/- SEM; P < 0.01). Histologically, the degree of rejection in group III was moderate compared with that in group II. On day 3, the LTB4 level in group II was significantly higher than that in group I (3361 +/- 985 vs. 407 +/- 70 pg/ml, P < 0.05), and the PGE2 level in group III was significantly higher than that in group 1 (50.3 +/- 4.8 vs. 23.5 +/- 4.7 pg/ml, P < 0.01) and in group II (32.9 +/- 4.2 pg/ml, P < 0.05). These findings suggest that AA-861 reduced liver allograft rejection by suppressing the elevation of 5-lipoxygenase products and increasing PGE2 production in the early stage of rejection.
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PMID:The immunosuppressive effect of 5-lipoxygenase inhibitor on liver allotransplantation in rats. 821 43

It is postulated that a vigorous host inflammatory response in the cystic fibrosis lung contributes to lung injury. Tumour necrosis factor-alpha (TNF-alpha) may play a part in that process and in the generation of leukotrienes. Therefore, the relationships between sputum TNF-alpha, leukotriene concentration, and lung function abnormalities in 16 children with cystic fibrosis were investigated. Each subject provided sputum samples and performed spirometry. TNF-alpha was measured by enzyme linked immunosorbent assay; individual leukotrienes were separated using high performance liquid chromatography and quantified by radioimmunoassay. The geometric mean concentration of TNF-alpha was 129.7 pg/ml and 95% confidence interval 48.2 to 348.3. Mean (SEM) leukotriene B4 (LTB4) was 97.8 (22.9) pmol/g and total cysteinyl leukotrienes were 60.9 (14.8) pmol/g. Mean (SD) forced expiratory volume in one second (FEV1) of the group was 53 (15)% of predicted and forced vital capacity (FVC) was 65 (14)% of predicted. There was a significant positive correlation between TNF-alpha and both LTB4 and the total cysteinyl leukotriene sputum content. An inverse relationship existed between TNF-alpha and FEV1 and FVC. Moreover, a negative correlation was observed between sputum LTB4 and FEV1 and FVC. These results suggest that TNF-alpha and the leukotrienes may participate in the airways inflammation and airflow obstruction observed in cystic fibrosis subjects and support the hypothesis that TNF-alpha upregulates the 5-lipoxygenase pathway in vivo.
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PMID:Sputum tumour necrosis factor-alpha and leukotriene concentrations in cystic fibrosis. 838 38

Exogenous eicosapentaenoic acid (EPA) has been compared with exogenous arachidonic acid (AA) for its ability to modulate the oxidative metabolism of membrane-derived arachidonic acid by the 5-lipoxygenase pathway in ionophore-activated human eosinophils, and for its suitability as a parallel substrate in this pathway. Products were quantitated by specific RIA and tetraene and pentaene leukotrienes (LT) were separated by reverse-phase HPLC. Eosinophils were preincubated with control buffer, exogenous EPA or AA and stimulated optimally with 10 microM calcium ionophore (A23187) for 15 min. Mean generation of LTC4 in the absence of fatty acid was 6.0 = 1.1 ng/10(6) eosinophils (mean = SEM, n = 5). In the presence of EPA, the amount of LTC4 generated rose to peak at 16.5 +/- 1.9 ng/10(6) eosinophils at 10 micrograms/ml EPA and then fell to 8.3 +/- 3.1 ng/10(6) cells at 40 micrograms/ml EPA. The EPA derivative, LTC5 was first detectable at 5 micrograms/ml EPA with 4.8 +/- 1.2 ng/10(6) cells and gradually rose with increasing dose of EPA to be maximal at 40 micrograms/ml with 12.7 +/- 2.2 ng/10(6) cells. Identity of the LTC5 was confirmed by an identical retention time to synthetic LTC5 standard, immunoreactivity to a specific antibody against LTC4 and LTC5 and a typical UV absorbance spectrum. When eosinophils were preincubated with AA and similarly stimulated, LTC4 generation gradually increased from a baseline of 6.7 +/- 0.7 ng/10(6) cells in the absence of fatty acid to reach a maximum of 12.9 +/- 0.8 ng/10(6) cells at 40 micrograms/ml of AA. Total LTC generation was nearly twofold more with cells incubated with EPA than with cells incubated with AA (p < 0.05). Thus, EPA does not suppress LTC generation from eosinophils but stimulates it at lower doses and is a substrate for LTC5 generation.
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PMID:Effects of exogenous eicosapentaenoic acid on generation of leukotriene C4 and leukotriene C5 by calcium ionophore-activated human eosinophils in vitro. 846 88

The expression of leukotriene C4 synthase (LTC4S) was examined during the development of eosinophils in vitro from cord blood mononuclear cells. At 7 days, the cells contained mRNA and sodium dodecyl sulfate-polyacrylamide gel electrophoresis immunoblot signals for cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase (5-LO), and 5-lipoxygenase-activating protein (FLAP), but lacked LTC4S and did not generate cysteinyl leukotrienes when stimulated with 20 mumol/L calcium ionophore. At 14 days, 94% of the cells were of eosinophil lineage, both LTC4S mRNA transcript and protein were present, and ionophore stimulation resulted in the generation of 23.9 +/- 6.0 pmol cysteinyl leukotrienes/10(6) eosinophil-lineage cells (mean +/- SEM, n = 6). At 28 days, progressive eosinophil maturation was accompanied by further increments in 5-LO, FLAP, and LTC4S proteins, and by the ionophore-induced production of 94.6 +/- 9.0 pmol cysteinyl leukotrienes/10(6) eosinophil-lineage cells (n = 6). Cells selected for CD34 expression lacked detectable 5-LO/LTC4S pathway proteins, and with culture generally expressed immunodetectable cPLA2 and 5-LO proteins by 3 days, FLAP protein by 7 days, and LTC4S protein by 10 days. Thus, during the development of eosinophils in vitro, cPLA2, 5-LO, and FLAP are expressed before LTC4S. Once the lineage is established by morphologic criteria, the eosinophilopoietic cytokines mediate upregulation of FLAP and LTC4S, members of a newly recognized gene family, and of 5-LO, during ongoing cell maturation.
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PMID:Expression of LTC4 synthase during the development of eosinophils in vitro from cord blood progenitors. 894 71

Leukotrienes have been implicated in the bronchoconstriction caused by indirect stimuli. In the present study we examined the effect of oral ABT-761, a novel 5-lipoxygenase (5-LO) inhibitor, on exercise- and adenosine (AMP)-induced bronchoconstriction in nine asthmatics. At the four 1-d, single-dose treatment periods, ABT-761 (200 mg) or placebo (P) was ingested 5 h before challenge in a double-blind, crossover fashion. At study periods 1 and 2 the subjects performed an exercise challenge and at study periods 3 and 4 an AMP challenge. Pretreatment with ABT-761 caused a significant inhibition of the maximal percentage fall of FEV1 from baseline (p = 0.037) and a reduction of the percentage fall in FEV1 (area under the curve, AUC) of 61.4 +/- 14.1% (mean +/- SEM) after exercise challenge (p = 0.021). Although pretreatment with ABT-761 did not significantly inhibit the maximal fall of FEV1 after AMP challenge (p = 0.134), the overall bronchoconstriction was significantly inhibited, the AUC being reduced by a mean (+/- SEM) of 82.7 +/- 7.2% (p = 0.012). There was no significant correlation between the protective effect against exercise and that against AMP for individual patients. The percentage change in urinary leukotriene E4 (LTE4) excretion at exercise was + 18.1 +/- 10.9% on placebo and -44.8 +/- 6.2% after ABT-761 (p = 0.017); changes at adenosine were + 38.5 +/- 27.0% on placebo and -36.7 +/- 9.8% after ABT-761 (p = 0.028). On placebo, exercise produced a marked stimulation of the ex vivo LTB4 production, whereas adenosine was associated with only a minor increase; ABT-761 caused a greater than 90% inhibition (p < 0.05 for both challenges). We conclude that ABT-761 is a potent and long-acting 5-LO inhibitor which significantly attenuates exercise- and adenosine-induced bronchoconstriction, indicating that leukotrienes are important mediators in both challenges.
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PMID:The effect of ABT-761, a novel 5-lipoxygenase inhibitor, on exercise- and adenosine-induced bronchoconstriction in asthmatic subjects. 911 20

Leukotrienes (LT) are potent vasoconstrictors in the pulmonary circulation. We have investigated the synthesis of LTC4 by intrapulmonary arteries and veins of perinatal lambs. Paired vessels of near-term fetal 146 +/- 2- and 2- to 7-day-old newborn lambs (each n = 7), were incubated for 10 min at 37 degrees C in baseline, with 1 mumol/L A32187 or 0.1 mmol/L arachidonic acid. Produced leukotriene C4 was assayed from media by ELISA. Baseline production of leukotriene (ng/mg tissue, means +/- SEM) by vessels for arteries was 0.006 +/- 0.001 and 0.059 +/- 0.009 for fetus and newborn, respectively. In veins, the values were 0.013 +/- 0.003 and 0.073 +/- 0.007 for fetus and newborn, respectively. On stimulation with the calcium ionophore A23187, production by arteries increased 25-fold in the fetus, but 4-fold in the newborn. The corresponding values for stimulated veins were 37-fold and 9-fold in fetus and newborn, respectively. Generally, production by veins was greater than production by the matching arteries. In all instances, the fetal vessels produced less leukotrienes than the newborn vessels. Western analysis of stimulated and unstimulated vessel membrane protein showed greater expression of 5-lipoxygenase in veins than in arteries (P < 0.05). Our data show that veins produce more LTC4 due to greater expression of 5-lipoxygenase in the vessels and thus suggest that veins of perinatal lamb lungs may be more susceptible to LT-induced vasoreactivity in the perinatal pulmonary circulation. We speculate that a higher production of LTC4 by fetal veins may be necessary to maintain a high venous tone in fetal lungs.
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PMID:Leukotriene synthesis by isolated perinatal ovine intrapulmonary vessels correlates with age-related changes in 5-lipoxygenase protein. 923 99

Our objective was to determine the effect of amphotericin B on leukotriene (LT) A4 hydrolase in human neutrophil cytosol and to examine its effect on intact neutrophils in vitro. Cytosolic fractions were assayed for LTA4 hydrolase and 5-lipoxygenase activity in the presence or absence of amphotericin B. The IC50 of amphotericin B for LTA4 hydrolase activity was 0.72 microM. No inhibition of 5-lipoxygenase activity in the cytosolic fraction was detected. The IC50 of amphotericin B for leukotriene B4 synthesis in intact neutrophils was 0.43 microM. The 5-hydro(per) oxy-eicosatetraenoic acid (5-H(P)ETE) synthesis was diminished in intact cells by 66.8 [3.4]% (mean[SEM]) in the presence of 0.01 mM amphotericin B. Thus, amphotericin B inhibited the synthesis of LTB4 and 5-H(P)ETE in neutrophils in vitro. Differences between the results of studies on cytosol and on intact cells suggest that amphotericin B is involved in a complex interaction in the intact cell.
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PMID:Inhibitory effect of amphotericin B on leukotriene B4 synthesis in human neutrophils in vitro. 957 47

We employed a bile duct ligation (BDL) model of cholestatic liver injury to test the hypothesis that this form of preexisting hepatic dysfunction alters the kinetics of circulating TNF-alpha and IL-6 after Escherichia coli endotoxemia, thereby augmenting mortality and lung injury by a TNF-alpha:leukotriene (LT) axis of inflammation. Male rats were catheterized 13 d after BDL or sham surgery and studied while awake 18 to 24 h later. Cholestasis after BDL was confirmed by baseline serum bilirubin (BDL = 7.34 +/- 0.72 mg/dl, mean +/- SEM, n = 17 versus Sham = 0.25 +/- 0.07, n = 20; p < 0.005) and histopathology. Sham and BDL animals received E. coli lipopolysaccharide serotype O55:B5 (LPS, 5 mg/kg i.v.) or 0.9% NaCl (NS) ending at t = 0 and were monitored over 24 h for vital signs and hemodynamics. In parallel studies, lipoxygenase inhibition was performed using diethylcarbamazine or the 5-lipoxygenase activating-protein inhibitor MK-886. Blood was collected at baseline and at t = 1.5, 3.5, and 24 h for formed elements and for serum endotoxin, TNF-alpha, IL-6, bilirubin, and alanine aminotransferase (ALT). Organs were evaluated at 24 h for histopathology, including neutrophil (PMN) densities and wet/dry weight (W/D) ratios. Cholestasis reduced survival after otherwise nonlethal endotoxemia, with seven of 11 BDL + LPS rats dying within 24 h versus no deaths in BDL + NS (n = 6), Sham + LPS (n = 14), or Sham + NS (n = 6) animals (p < 0.01). Despite equivalent serum endotoxin between groups, circulating TNF-alpha was 8-fold higher in BDL + LPS than in Sham + LPS rats at 1.5 and 3.5 h (p < 0.001), whereas serum TNF-alpha did not differ between BDL + NS and Sham + NS rats. IL-6 likewise was increased differentially by 1.5 h in BDL + LPS animals (11.98 +/- 2.42 ng/ml) versus Sham + LPS rats (3.05 +/- 0.58 ng/ml, p < 0.05). Hypothermia, bradycardic hypotension, and leukopenia were most severe and prolonged in BDL + LPS rats, which also had significantly higher ALT values, W/D ratios, and organ PMN counts. LT inhibition failed to reduce BDL-related differences in serum cytokines or survival after endotoxemia. Thus, cholestasis augments inflammatory responses to gram-negative endotoxemia, sensitizing the host to enhanced fluid flux in multiple organs and to mortality by a LT-independent mechanism.
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PMID:Cholestatic liver injury increases circulating TNF-alpha and IL-6 and mortality after Escherichia coli endotoxemia. 960 37


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