Disease relevance of leukotriene E4

• Cyclooxygenase blockade elevates leukotriene E4 production during acute anaphylaxis in sheep [1].
• Whole blood LTE4 synthesis was increased in kwashiorkor patients by a factor of 3.5 (p < 0.01) [2].
• The urinary LTE4 values of the rhinitis patients were within the normal range whether or not they had symptoms [3].
• Accordingly, urinary excretion of leukotriene E4 (LTE4), the major urinary metabolite of peptide leukotrienes in humans, was measured in patients admitted to the hospital with evidence of acute myocardial ischemia to assess in vivo release of 5-lipoxygenase products during and after the ischemic episode [4].
• Urinary LTE4 excretion at admission for chest pain was also elevated in 14 patients having unstable angina (UA; 370 +/- 125 pg LTE4/mg creatinine sulfate) [4].

High impact information on leukotriene E4

• The increased levels of the biologically active, proinflammatory mediators LTE4 and LTB4 might be of pathophysiological significance in peroxisome deficiency disorders [5].
• Urinary LTE4 excretion was significantly higher in patients with kwashiorkor than in controls (118.8 [SD 28.5] vs 31.1 [19.3] nmol/mol creatinine; p < 0.01) [2].
• However, using laser-Doppler flowmetry, leukotrienes C4 and D4 were found, when administered intraarterially at doses in the 0.05-1.0 micrograms/kg per min range, to produce dose-dependent reductions of gastric blood flow while N-acetyl leukotriene E4 was without effect and leukotriene B4 induced slight increases [6].
• Urinary LTE4, a stable urinary end-product of LTC4 and LTD4, was measured, by means of high-performance liquid chromatography and radioimmunoassay [3].
• Mean urinary LTE4 was higher in the asthmatic patients (78.3 [46.5-131.8] ng/mmol creatinine) than in normal subjects (p less than 0.01), although there was substantial overlap into the normal range [3].

Chemical compound and disease context of leukotriene E4

• Furthermore, our data suggest that the LTD4-induced mobilization is regulated by a pertussis toxin-insensitive G-protein whereas the LTE4-induced mobilization is relatively insensitive to both pertussis toxin and GDP beta S [7].
• Leukotriene A4 may also react to form leukotriene C4 (a natural component of slow-reacting substance of anaphylaxis), leukotriene D4, leukotriene E4, and the 11-trans-isomers [8].
• To assess the role of sulfidopeptide leukotrienes in the pathogenesis of exercise-induced asthma (EIA), the urinary levels of leukotriene E4 (LTE4), a metabolite of LTC4 and LTD4, were measured by RIA before and after exercise in 13 children with EIA and 10 healthy children [9].
• The increased production by stimulated lungs during hypoxia of LTE4, a substance that may increase lung capillary permeability, and that of LTB4, a powerful chemoattractant, may be important contributing factors to lung injury [10].
• Urinary leukotriene E4, the major metabolite of leukotrienes C4 and D4, was elevated in patients with hepatorenal syndrome (17.8 ng/h) when compared with normal controls (5.1 ng/h) or subjects with renal failure alone (1.9 ng/h) [11].

Biological context of leukotriene E4

• All peptidyl LTs (LTC4, LTD4, and LTE4) inhibited B-1 F cell growth in a dose-dependent manner and exhibited maximum inhibition of DNA synthesis (60-80%) compared with that of untreated cells in a range of 10(-9) to 10(-8) M [12].
• There is little conversion to LTC4 to LTE4 in purified preparations of basophils, but conversion to LTE4 does occur if cell densities are high during incubation [13].
• LTE4 causes very long-lasting bronchoconstriction [14].
• Inhalation challenges with either synthetic LTC4 or LTE4 were performed after prior inhalation of aerosolized SK&F 104353 or placebo in a double-blind, randomized fashion [15].
• METHODS: A group of eight patients with asthma shown to have adverse reactions to aspirin documented by a 15% or greater decrease in forced expiratory volume in 1 second, accompanied by an elevation in urinary leukotriene E4 after ingestion of aspirin, received aspirin or placebo in a study with a crossover design [16].

Anatomical context of leukotriene E4

• Experiments in which the SV was pretreated with L-NG-monomethyl-L-arginine (L-NMMA; 10(-4) mol/L) or indomethacin (10(-5) mol/L) or was denuded of endothelium had no significant effect on the Emax values for LTE4 [17].
• The mutant mice retain partial ability to convert LTD4 to LTE4, ranging from 80-90% of the wild-type values in small intestine and liver to 16% in kidney and 40% in lung, heart, and pancreas [18].
• Synthetic LTB4, LTC4, LTD4, and LTE4 were administered over 1-min periods to the isolated, perfused rat pancreas in the presence of 5.6 mM glucose [19].
• Metabolism of leukotriene E4 in isolated rat hepatocytes. Identification of beta-oxidation products of sulfidopeptide leukotrienes [20].
• The data that support this conclusion are: 1) LTE4 completely displaced [3H]LTD4 from its receptors in U-937 cell membranes [21].

Associations of leukotriene E4 with other chemical compounds

• Tritiated leukotriene C4 and leukotriene E4 (10 nmol/L) were infused for 5 minutes, and metabolites in bile were determined by high-pressure liquid chromatography [22].
• Whereas no difference was found for LTE4, SSc fibroblasts produced significantly higher amounts of LTB4 after stimulation, compared with healthy control fibroblasts [23].
• We have shown previously that stromal cells isolated from a human giant cell tumor secrete 5-HETE (5-hydroxyeicosatetraenoic acid) and the peptido-leukotrienes, also known as the cysteinyl leukotrienes LTC4, LTD4, and LTE4 [24].
• These results suggest that the LTE4 precursors, LTC4 and LTD4, are important bronchoconstrictor mediators causing EARs after allergen inhalation [25].
• Salmeterol significantly attenuated aspirin-precipitated bronchoconstriction and the increase in urinary LTE4 [26].

Gene context of leukotriene E4

• We assessed the basal levels of urinary LTE4, the increment of urinary LTE4 on venous aspirin challenge, and LTC4S activity in peripheral blood eosinophils [27].
• Neuropeptide Y and galanin, both present in airways, enhanced the levels of LTD4 and had no effect on LTC4 or leukotriene E4 (LTE4) levels [28].
• Serum LTB4, LTC4, IL-2, IL-4, IFN-gamma and urinary LTE4 levels were detected by enzyme-linked immunosorbent assay (ELISA) and LTB4, LTC4, LTE4 concentrations of cutis tissue were measured by reverse-phase high-pressure liquid chromatography (RP-HPLC) in 10 eczema patients and 10 healthy volunteers [29].
• In addition, the study involved evaluation of a leukotriene E4 analogue, BAY u9773, suggested to inhibit responses which cannot be blocked by CysLT1-receptor antagonists [30].
• These observations demonstrate that the conversion of LTD4 to LTE4 and the degradation of cys-bis-gly are catalyzed by at least two alternative pathways (one of which is MBD) that complement each other to varying extents in different tissues [18].

Analytical, diagnostic and therapeutic context of leukotriene E4

• To evaluate the ratio of hepatobiliary to renal elimination of leukotrienes noninvasively by positron emission tomography (PET), we synthesized N-[11C]acetyl-leukotriene E4 by chemical N-acetylation of leukotriene E4 [31].
• Cysteinyl leukotriene synthesis was assessed by measuring the excretion of leukotriene E4 (LTE4) in urine by radioimmunoassay [32].
• This study identifies the microvascular target of leukotriene E4 (LTE4) by vascular labeling with carbon black and establishes the mechanism of its action at the cellular level by electron microscopy [33].
• Radioactivity quickly appeared in the urine with 10-16% eliminated during the first 2 h following intravenous infusion; 7%, 2-5 h; 4%, 5-8 h; 4%, 8-15 h; and 1.5%, 15-24 h from the [14C] LTE4 experiments [34].
• After in vitro stimulation of the blood cells with grass and birch pollen allergens, SLT release (LTC4, LTD4, and LTE4) was quantified by using the ELISA technique [35].

References