leukotriene-e4 and Hypoxia

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Humans; Hypoxia; Leukotriene B4; Leukotriene E4; Lung; Microcirculation; SRS-A; Vasoconstriction

Previous research has demonstrated that blood and urine concentrations of various leukotrienes are elevated with acute hypoxic exposure. Some of these studies have suggested that leukotrienes may be mediators in the pathogenesis of acute mountain sickness (AMS). We conducted a randomized, double-blind study to determine if AMS symptoms correlated with the increase in leukotriene synthesis and if prophylactic leukotriene receptor blockade would prevent the development of AMS in a simulated high altitude exposure. Three male and five female subjects completed two normobaric hypoxia chamber exposures (average F(IO2) 12.4 +/- 0.09%), receiving montelukast 10 mg daily for 4 days prior to one session and placebo for 4 days prior to the other session. There were no differences in Lake Louise AMS scores, time spent in the chamber, average oxygen saturation, and average heart rate during the montelukast and placebo sessions. Headache scores were higher during treatment with montelukast than during treatment with placebo. Compared to preexposure values, urinary leukotriene E4 concentrations were unchanged during the hypoxic chamber exposure following treatment with placebo or montelukast. Urinary leukotriene E4 excretion during the hypoxic exposure did not differ between the two sessions. A 4-day course of leukotriene receptor blockade does not prevent symptoms of AMS. These results suggest that leukotrienes do not play a causal role in the pathophysiology of AMS.

Topics: Acclimatization; Acetates; Administration, Oral; Adult; Altitude Sickness; Atmosphere Exposure Chambers; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Female; Humans; Hypoxia; Leukotriene Antagonists; Leukotriene E4; Male; Premedication; Quinolines; Severity of Illness Index; Statistics, Nonparametric; Sulfides

Low-grade inflammation may potentially explain the relationship between obstructive sleep apnea syndrome (OSA) and cardiovascular events. However, the respective contribution of intermittent hypoxia and confounders, such as obesity, is still debated.. To monitor urinary leukotriene E(4) (U-LTE(4)), a validated marker of proinflammatory cysteinyl leukotriene production, in OSA; to determine the influence of obesity and other confounders on U-LTE(4) concentrations; to examine the mechanisms involved through transcriptional profiling of the leukotriene pathway in peripheral blood mononuclear cells (PBMCs); and to investigate the effect of continuous positive air pressure (CPAP) on U-LTE(4) concentrations.. We measured U-LTE(4) by liquid chromatography-tandem mass spectrometry.. The U-LTE(4) concentrations were increased (P = .019) in 40 nonobese patients with OSA carefully matched for age, sex, and body mass index (BMI) to 25 control subjects, and correlated (r = 0.0312; P = .017) to the percentage of time spent with mean oxygen saturation (SaO(2)) less than 90%. In a larger cohort of patients with OSA (n = 72), U-LTE(4) increased as a function of BMI (r = 0.445; P = .0002). In those patients, the expression levels of 5-lipoxygenase activating protein mRNA in mononuclear cells exhibited a similar pattern. A stepwise multiple linear regression analysis performed in this cohort identified BMI (P = .001; regression coefficient, 3.33) and percentage of time spent with SaO(2) <90% (P = .001; regression coefficient, 1.01) as independent predictors of U-LTE(4) concentrations. Compared with baseline, CPAP reduced by 22% (P = .006) U-LTE(4) concentrations only in patients with OSA with normal BMI.. Obesity, and to a lesser extent hypoxia severity, are determinant of U-LTE(4) production in patients with OSA.

Topics: 5-Lipoxygenase-Activating Proteins; Adult; Carrier Proteins; Chromatography, Liquid; Female; Humans; Hypoxia; Leukotriene E4; Male; Membrane Proteins; Middle Aged; Obesity; Polysomnography; Prospective Studies; RNA, Messenger; Sleep Apnea, Obstructive; Tandem Mass Spectrometry; Thromboxane B2

We examined whether lung inflammatory mediators are increased during exercise and whether pharmacological blockade can prevent exercise-induced arterial hypoxemia (EIAH) in young athletes. Seventeen healthy athletes (9 men, 8 women; age 23 +/- 3 yr) with varying degrees of EIAH completed maximal incremental treadmill exercise tests after administration of fexofenadine, zileuton, and nedocromil sodium or placebo in a randomized double-blind crossover study. Lung function, arterial blood gases, and inflammatory metabolites in plasma, urine, and induced sputum were assessed. Drug administration did not improve EIAH or gas exchange during exercise. At maximal exercise, oxygen saturation fell to 91.4 +/- 2.6% (drug trial) and 91.9 +/- 2.1% (placebo trial) and alveolar-arterial oxygen difference widened to 28.1 +/- 6.3 Torr (drug trial) and 29.3 +/- 5.7 Torr (placebo trial). Oxygen consumption, ventilation, and other exercise variables were similarly unaffected by drug treatment. Although plasma histamine increased with exercise, values did not differ between trials, and urinary leukotriene E(4) and 11beta-prostaglandin F(2alpha) levels were unchanged after exercise. Postexercise sputum revealed no significant changes in markers of inflammation. These results demonstrate that EIAH in young athletes is not attenuated with acute administration of drugs targeting histamine and bioactive lipids. We conclude that airway inflammation is of insufficient magnitude to cause impairments in gas exchange and does not appear to be linked to EIAH in healthy young athletes.

Topics: Adult; Cell Count; Exercise; Female; Histamine H1 Antagonists; Humans; Hydroxyurea; Hypoxia; Inflammation Mediators; Leukotriene Antagonists; Leukotriene E4; Lung; Male; Oxygen Consumption; Pulmonary Gas Exchange; Respiratory Function Tests; Sports; Sputum; Terfenadine

To determine whether urinary leukotriene E4 (uLTE4) levels increase upon exposure to high altitude, and also to ascertain the relationship between uLTE4 levels and symptoms of acute mountain sickness (AMS).. Prospective, unblinded, single-factor (altitude) experimental study.. US Army research laboratory facilities at sea level ([SL] 50 m), 1,830 m, and 4,300 m.. Eight healthy male subjects ranging in age from 19 to 24 years.. uLTE4 levels and symptoms of AMS were measured at just above SL (50 m), 3 1/2 days after being transported from SL to moderate altitude (MA) (1,830 m), and 1 1/2 days after ascent from 1,830 to 4,300 m (high altitude [HA]). Symptoms of AMS were assessed using standard indexes derived from the Environmental Symptoms Questionnaire weighted toward cerebral (AMS-C) and respiratory (AMS-R) manifestations. Oxygen saturation was measured noninvasively by pulse oximetry at SL and HA.. The mean (+/-SEM) uLTE4 levels (pg/mg creatinine) were 67.9 (+/-13.2) at SL; 82.3 (+/-5.5) at MA; and 134.8 (+/-19.4) at HA (p < 0.05 comparing HA with SL and MA).. We conclude that uLTE4 levels increase shortly after exposure to HA even after staging for 4 days at MA. Although this study does not clearly demonstrate a relationship between uLTE4 levels and symptoms of AMS, it supports the hypothesis that leukotrienes may be involved in the pathophysiologic state of AMS.

Topics: Adult; Altitude; Altitude Sickness; Humans; Hypoxia; Leukotriene E4; Male; Prospective Studies

Uptake, metabolism and biliary elimination of infused cysteinyl leukotrienes were investigated in single-pass perfused rat liver. Hypoxia did not impair uptake of infused [3H]leukotriene C4, but inhibited biliary excretion of radioactivity by about 50% compared with normoxic control experiments. In addition, the leukotriene metabolite pattern in bile was profoundly altered and was characterized in hypoxia by a 75% to 80% decrease of both leukotriene C4 and polar metabolites, representing omega-oxidation products, whereas the appearance of leukotriene D4 in bile was not affected. Reoxygenation was followed by a marked increase of biliary excretion of polar metabolites, indicating that leukotrienes taken up and stored in the liver cells during the hypoxic period now underwent omega-oxidation with subsequent elimination of the omega-oxidized products. Hypoxia also inhibited the biliary excretion of radioactivity after [3H]leukotriene E4 addition because of an almost complete absence of omega-oxidation products in bile, whereas N-acetyl-leukotriene E4 excretion was not affected. Induction of liver injury by carbon tetrachloride treatment decreased single-pass uptake of [3H]leukotriene C4 by 30%, and only 36% of the radioactivity taken up by the liver was eliminated into bile within 1 hr, compared with 78% in normal livers. The pattern of biliary leukotriene metabolites, however, was not significantly different. Lowering the pH in the perfusion medium from 7.4 to 7.1 had no effect on uptake, metabolism or biliary elimination of infused [3H]leukotriene C4. The data show that hypoxia and experimental liver injury, but not acidosis, impair hepatic processing of cysteinyl leukotrienes. Thus, in leukotriene-induced shock syndromes, leukotriene elimination and inactivation may be impaired giving rise to a "vicious circle."

Topics: Acidosis; Animals; Bile; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Hypoxia; In Vitro Techniques; Leukotriene E4; Leukotrienes; Liver Diseases; Male; Perfusion; Rats; Rats, Inbred Strains; SRS-A

Although the mechanism underlying hypoxic pulmonary vasoconstriction remains undefined, various reports have suggested that mast cells and cell-derived mediators may be important in the production of this phenomenon. We investigated the effect of reducing oxygen tension on the release from human lung fragments of the mast cell-derived mediators histamine, prostaglandin (PG) D2 and peptide leukotrienes, as well as the release of the largely non-mast cell-derived mediators PGE2, PGF2 alpha, prostacyclin metabolite (6-keto-PGF1 alpha) and the thromboxane A2 metabolite (thromboxane B2). The effect of reducing oxygen tension on both basal mediator release and release triggered by goat antihuman immunoglobulin E was studied. Reducing pO2 of buffer in which lung fragments were placed from 161 to 54 mm Hg resulted in no spontaneous release of histamine, PGD2 or peptide leukotrienes. However, hypoxia had a marked effect on mediator release triggered by goat antihuman immunoglobulin E. Although net histamine release was relatively unaffected (control 13.9 +/- 2.7%, hypoxic 12.7 +/- 2.1%), hypoxic treatment resulted in an 89% inhibition of PGD2 release (control 47.7 +/- 17.4 ng/g of lung, hypoxic 5.26 +/- 1.91 ng/g of lung) and an 81% inhibition of peptide leukotriene release (control 22.5 +/- 7.6 ng/g of lung, hypoxic 4.37 +/- 2.4 ng/g of lung). Similar inhibition was seen for non-mast cell-derived mediators, including PGF2 alpha, prostacyclin metabolite and thromboxane B2, and probably for PGE2. We conclude that hypoxic treatment of human lung fragments in vitro results in no spontaneous release of preformed or newly formed mediators but that it markedly alters mediator release after goat antihuman immunoglobulin E triggering.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Histamine Release; Humans; Hypoxia; Immunoglobulin E; Leukotriene E4; Lung; Mast Cells; Oxygen; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins D; SRS-A; Thromboxane A2; Thromboxane B2