leukotriene-e4 and Bronchial-Hyperreactivity

Leukotriene (LT) E(4) mediates many of the principal features of bronchial asthma, such as bronchial constriction, hyperresponsiveness, eosinophilia, and increased vascular permeability. Furthermore, it is the most stable of the cysteinyl leukotrienes (CysLTs) and can be active at the site of release for a prolonged time after its synthesis. There might be several reasons why LTE(4) has been forgotten. LTE(4) demonstrated low affinity for CysLT(1) and CysLT(2) receptors in equilibrium competition assays. It was less potent than other CysLTs in functional assays, such as calcium flux, in cells transfected with CysLT(1) and CysLT(2). The introduction of CysLT(1) antagonists into clinical practice diverted interest into CysLT(1)-related mechanisms, which were mediated mainly by LTD(4). However, experiments with animal models and human studies have revealed that LTE(4) has unique characteristics that cannot be explained by the current knowledge of CysLT(1) and CysLT(2). These activities include its potency relative to other CysLTs to increase airway responsiveness to histamine, to enhance eosinophilic recruitment, and to increase vascular permeability. Asthmatic airways also demonstrate marked in vivo relative hyperresponsiveness to LTE(4), especially in patients with aspirin-sensitive respiratory disease. This has stimulated a search for additional LT receptors that would respond preferentially to LTE(4) stimulation.

Topics: Animals; Aspirin; Asthma; Bronchial Hyperreactivity; Drug Hypersensitivity; Histamine; Humans; Leukotriene C4; Leukotriene D4; Leukotriene E4; Methacholine Chloride; Receptors, Leukotriene; Skin

Beta-adrenoceptor agonists have several pharmacological actions in the lung which affect airway function. They have a direct relaxant effect on human bronchial smooth muscle and several additional properties, including attenuation of mast cell mediater release, reduction in airway microvascular leakage, and inhibition of cholinergic neurotransmission within the airway, in vitro. However, direct evidence in vivo for any anti-inflammatory effects of beta-adrenocepter agonists is limited. We reported that beta-agonists (procaterol, salmeterol) inhibited significantly I. A. R. and L. A. R. Salmeterol also reduced urinary secretion of LTE4. It is suggested that beta-agonists have some of anti-allergic effects in the clinical pharmacological study. From recent clinical studies, it is recommended on demand use more than regular use of inhaled beta-agonists.

Topics: Adrenergic beta-Agonists; Albuterol; Anti-Allergic Agents; Asthma; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Humans; In Vitro Techniques; Inflammation Mediators; Intercellular Adhesion Molecule-1; Leukotriene E4; Mast Cells; Procaterol; Salmeterol Xinafoate

Fourteen-membered macrolides, such as roxithromycin, have been reported to exhibit other pharmacological activity including anti-asthmatic effects, besides antibiotic activity.. This study was designed to investigate the protective effect of roxithromycin on airway responsiveness to the sulpyrine provocation test and to investigate whether this protective activity is associated with a reduction in aspirin-induced excretion of urinary leucotriene E4 (u-LTE4), a marker of cysteinyl leucotriene overproduction that participates in the pathogenesis of aspirin-intolerant asthma. Also, the present study was designed to examine whether or not its anti-asthmatic activity was associated with a reduction in eosinophilic inflammation.. For 8 weeks before analysis, subjects received 150 mg of roxithromycin or matching placebo twice daily. We assessed the effects of pretreatment with roxithromycin on bronchoconstriction precipitated by inhalation of sulpyrine in 14 adult patients with mild or moderate aspirin-intolerant asthma; those who were in stable clinical condition and were hyperresponsive to sulpyrine provocation test were allocated to this study. A double-blind, randomized, crossover design was used. Urinary LTE4 was measured by a combined reverse-phase high-performance liquid chromatography (rp-HPLC) enzyme immunoassay on sulpyrine provocation testing day. Blood and sputum samples were taken in the morning on the sulpyrine provocation testing day. Eosinophil counting and measurement of eosinophilic cationic protein (ECP) were performed.. After the 8 weeks of treatment with roxithromycin, patients' symptoms, blood eosinophils, serum ECP, sputum eosinophils, and sputum ECP were significantly decreased. On the other hand, values of PC20-sulpyrine did not improve after roxithromycin at all. Furthermore, although challenge with sulpyrine caused a significant increase in u-LTE4, pretreatment with roxithromycin or placebo did not affect excretion of u-LTE4.. Although roxithromycin does not have antileucotriene effects, it has an antibronchial inflammatory effect associated with eosinophilic infiltration. This study raises further interesting therapeutic possibilities and warrants further trials of new approaches to the treatment of aspirin-intolerant asthma.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Blood Proteins; Bronchial Hyperreactivity; Bronchial Provocation Tests; Chromatography, High Pressure Liquid; Cross-Over Studies; Dipyrone; Double-Blind Method; Eosinophil Granule Proteins; Eosinophils; Female; Humans; Leukotriene E4; Male; Middle Aged; Ribonucleases; Roxithromycin

This study was designed to investigate the protective effect of cromolyn sodium on airway sensitivity to sulpyrine, and bronchial responsiveness to methacholine, and to investigate whether this protective activity is associated with reduction in aspirin-induced excretion of urinary leukotriene E4 (u-LTE4), a marker of the cysteinyl LT overproduction that participates in the pathogenesis of aspirin-induced asthma. We assessed the effects of pretreatment with cromolyn sodium on bronchoconstriction precipitated by inhalation of methacholine and sulpyrine in 16 adult patients with mild or moderate aspirin-intolerant asthma; those who were in stable clinical condition and were hypersensitive to a sulpyrine provocation test were included in this study. A double-blind, randomized, crossover design was used. u-LTE4 was measured using combined reverse-phase high-performance liquid chromatography enzyme immunoassay. Cromolyn sodium protected against analgesic-induced bronchoconstriction through mechanisms that are not related to its bronchodilator property, but to the improvement of both bronchial hyperresponsiveness and hypersensitivity to analgesics (p<0.01 and p<0.001). Although excretion of u-LTE4 did not increase after the methacholine provocation test, it significantly increased after sulpyrine provocation (p<0.01). Furthermore, after pretreatment with cromolyn sodium, the maximum level of u-LTE4 after the sulpyrine provocation test was significantly lower than in controls (p<0.01). These results support the hypothesis that cysteinyl LT is one of the most important components in the pathogenesis of aspirin-intolerant asthma. Cromolyn sodium improves both hypersensitivity to analgesics, and bronchial hyperresponsiveness in aspirin-intolerant asthma.

Topics: Adult; Anti-Asthmatic Agents; Aspirin; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Chromatography, High Pressure Liquid; Cromolyn Sodium; Cross-Over Studies; Dipyrone; Double-Blind Method; Female; Humans; Leukotriene E4; Male; Methacholine Chloride; Middle Aged

Asthmatic subjects who are resident at altitude may experience a deterioration in lung function following a stay at sea level. To determine whether measurement of urinary leukotriene E4 (LTE4) reflects changes in asthma severity and airway responsiveness, 14 allergic asthmatic subjects resident at altitude (1560 m, Davos, Switzerland) were studied. Subjects were randomly divided into two groups. Measurements of baseline forced expiratory volume in one second (FEV1), the concentration of histamine producing a 20% decrease in FEV1, (PC20 FEV1), serum total immunoglobulin E (IgE), eosinophil count, and urinary LTE4 concentration were determined prior to and following a 2 week stay in The Netherlands (sea level) in eight subjects (4 males and 4 females, aged 14 +/- 0.5 yrs) (mean +/- SEM) and over a similar time period in six subjects (4 males and 2 females, aged 15 +/- 0.3 yrs) resident in Davos, Switzerland. There was no significant difference in total IgE and eosinophil count, and no significant correlation between urinary LTE4 and PC20FEV1 histamine, FEV1, total IgE, and eosinophil count. In subjects returning to Davos from The Netherlands there was a significant increase in urinary LTE4 from a baseline value of 16.9 pg.mg-1 creatinine (GM, range 0.3-101.7 pg.mg-1 creatinine) to 52.3 pg.mg-1 creatinine (GM, range 8.8-301.6 pg.mg-1 creatinine), a significant decrease in PC20FEV1 from 1.7 mg.ml-1 (GM, range 0.3-16.4 mg.ml-1) to 0.9 mg.ml-1 (GM, range 0.1-->32 mg.ml-1), and a significant fall in FEV1 from 3.0 +/- 0.3 to 2.8 +/- 0.3 l (mean +/- SEM).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Altitude; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Child; Eosinophils; Female; Forced Expiratory Volume; Histamine; Humans; Immunoglobulin E; Leukocyte Count; Leukotriene E4; Male; Netherlands; Prospective Studies; Switzerland

The effect of indomethacin on the capacity of LTE4 to enhance airway histamine responsiveness was evaluated in eight mild asthmatic subjects. Subjects attended the laboratory on three separate pairs of study days when inhalation challenges with methacholine or LTE4 were performed and the airway responses to histamine were measured 4 and 7 h later. An open pair of study days was followed by a pair of study days during ingestion of either placebo or indomethacin capsules. The dose of agonist that produced a 35% fall in specific airways conductance (PD35 SGaw) was obtained by linear interpolation from the logarithmic dose-response curve. Indomethacin treatment did not affect baseline SGaw or methacholine airway responsiveness. However, indomethacin significantly inhibited LTE4-induced histamine hyperresponsiveness. Maximum enhancement of histamine responsiveness by LTE4 on the open and placebo study days was 4.1 +/- 0.9- (mean +/- SEM) and 5.7 +/- 1.2-fold, respectively (p = 0.36). Maximal enhancement on the indomethacin day was 1.68 +/- 0.46, and this was significantly decreased compared with that on the placebo day (p = 0.02). This suggests that LTE4-induced enhanced responsiveness to histamine is mediated in part by cyclooxygenase pathway-derived products.

Topics: Adult; Airway Resistance; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Female; Histamine; Humans; Indomethacin; Leukotriene E4; Male; Methacholine Chloride; SRS-A

Salmeterol (SM) is a novel beta 2-adrenoceptor agonist with a duration of action in excess of 12 hours. Evidence from in vitro studies has also demonstrated that, unlike the short-acting beta 2-agonists, such as salbutamol (SB), it may have some anti-inflammatory properties. With a randomized, double-blind, crossover design, we have compared the inhibitory effects of SM (50 micrograms) and SB (200 micrograms) delivered by metered-dose inhaler on allergen-induced bronchoconstriction, changes in airway reactivity, and urinary leukotriene (LT) E4 excretion in 12 atopic subjects with mild asthma. The immediate bronchoconstriction to allergen was significantly reduced by both beta 2-agonists (p less than 0.005), when reduction was expressed either in terms of maximum fall in FEV1 at 15 minutes after allergen (percent fall in FEV1, mean +/- SEM: 6.2 +/- 4.9, SM; 5.7 +/- 2.5, SB; 40.4 +/- 6.3, placebo) or the area under the FEV1 time curve (AUC) for the first 120 minutes after allergen. Four hours after challenge, results in the SB-treated and placebo-treated groups were not significantly different and demonstrated a small persistent bronchoconstriction compared to bronchodilatation in the SM-treated group (percent fall in FEV1, respectively, 9.3 +/- 3.7, 14.3 +/- 7.1, and -6.3 +/- 2.7; p less than 0.005, SM versus SB; p less than 0.02, SM versus placebo). Expressed in terms of AUC, only SM significantly reduced bronchoconstriction in the period 120 to 240 minutes after allergen (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic beta-Agonists; Albuterol; Allergens; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Double-Blind Method; Humans; Hypersensitivity, Immediate; Leukotriene E4; Salmeterol Xinafoate; SRS-A; Time Factors

Increased levels of leukotrienes (LTs) in exhaled breath condensate (EBC) are associated with asthma and bronchial hyperresponsiveness (BHR), whereas eicosanoids generated through the 15-lipoxygenase (LO) pathway (15-hydroxyeicosatetraenoic acid [HETE] and eoxins) have been less studied.. We investigated whether metabolites of the 5- and 15-LO pathways in EBC are associated with childhood asthma, asthma severity, and clinical parameters.. The present study included 131 school-aged children (27 children with problematic severe asthma, 80 children with mild-to-moderate asthma, and 24 healthy children) from the Severe Asthma Recognized in Childhood study and 19 children with other nonasthmatic chronic lung diseases. Clinical work-up included spirometry, fractional exhaled nitric oxide measurements, skin prick testing, and methacholine challenge. Eicosanoids were analyzed in EBC by using mass spectrometry and are reported as concentrations (in picograms per milliliter) and eicosanoid/palmitic acid (PA) ratios.. Eoxin C₄/PA, eoxin D₄/PA, eoxin E₄/PA, 15-HETE/PA, and LTC₄/PA ratios were significantly increased in asthmatic versus healthy children. Eoxin D₄/PA and LTE₄/PA ratios were also significantly higher in children with BHR. A nonsignificant trend was observed toward higher eoxin/PA ratios with increasing asthma severity. In contrast to asthma, children with chronic lung disease had the highest 15-HETE/PA, LTC₄/PA, LTE₄/PA, and LTB₄/PA ratios.. The results point to increased activity of the 15-LO inflammatory pathway in childhood asthma. Mass spectrometric analyses of EBC demonstrate that increased eoxin levels not only accompany the increased 5-LO product LTC₄ but are also associated with BHR. These markers might represent a new therapeutic target for asthma treatment.

Topics: Adolescent; Arachidonate 15-Lipoxygenase; Asthma; Breath Tests; Bronchial Hyperreactivity; Child; Exhalation; Female; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Leukotriene C4; Leukotriene E4; Leukotrienes; Male; Mass Spectrometry; Severity of Illness Index

Aspirin induced asthma (AIA) is a syndrome characterised by intolerance to acetylsalycilic acid (ASA), nasal polyps and bronchial asthma, being the metabolic shift of arachidonic acid toward the lipoxygenase pathway and hyper-production of cysteinyl-leukotrienes (cys-LTs) the current pathogenetic hypothesis. The research for both sensitive indicators and safe diagnostic tests is still attracting. Aim of the study was to compare the levels of urinary LTE4 in baseline and after Nasal Provocation Test (NPT) with L-ASA from subjects affected by aspirinin-Intolerance and characterized by only a nasal response to ASA to those from subjects with both a nasal and a bronchial response to the same challenge.. After their written consent, 74 subjects with mill to moderate AIA (16 male, mean age 45.3 years +/- 12.3 sd, mean basal FEV1 = 78.1% pred. +/- 6.2.4sd, FEV1 reversibility = 14.3% bsln +/- 2.1 ds after salbutamol 200 mcg) performed a NPT with L-ASA (total maximal dose 25 mg). Spirometry (FEV1), acoustic rinometry (nasal volume--VOL; nasal Resistance--Req; AR; TM Hood Lab., USA), and urinary LTE4 (Cayman Chemical, MI, USA, via Triturus System, Grifols, Spain) were checked in all subjects in basal conditions and 90' after NPT.. t test between means +/- sd, assuming p < 0.05, and linear regression between all variables considered.. In 69 ASA-intolerant-asthmatics, mean FEV1 did not change significantly following NPT (78.7% pred. +/- 5.1 sd in baseline; 78.5% pred. +/- 4.1 sd after NPT, p = ns) even though in the presence of a significant decrease of VOL. (12.6 cm3 +/- 4.1 sd in baseline; 6.2 cm3 +/- 4.6 sd after NPT, p = 0.003); of a substantial increase in Req (0.9 cm H2O/l/min +/- 0.1 ds in baseline; 2.4 cmH2O/l/min +/- 0.2 after NPT, p = 0.04), and of urinary LTE4 excretion (333.0 pg/mg +/- 161.7 in bsln; 558.0 pg/mg +/- 171.690' after NPT with L-SA, p = 0.02). In only 5 subjects, the nasal response occurred concomitantly to a significant bronco-constriction after the NPT: mean FEV, changed from 77.9% pred. +/- 3.9 in bsln to 46.6% pred. +/- 4.3 after NPT (p < 0.001); mean VOL from 13.9 cm3 +/- 4.7 sd to 5.6 cm3 +/- 2.8 sd (p < 0.001); mean Req from 1.1 cmH2O/l/min +/- 0.2 in bsln to 2.5 cmH2O/l/min +/- 0.4 after NPT (p = 0.02) in these subjects. In ASA-intolerant bronchial responders, the severity of respiratory reactions proved related to the extent of urinary LTE4 response, which on the other hand, proved significantly higher than that observed in ASA-intolerant subjects with only nasal response and in ASA-tolerant subjects (LTE4 from 333.0 pg/mg +/- 161.7 in baseline up to 558.0 pg/mg +/- 171.6 90 min. following the NPT with L-ASA the nasal-responders, p = 0.04, but from 412.0 pg/mg +/- 102.8 in baseline up to 978.0 pg/mg +/- 108.7 after NPT in bronchial responders, p < 0.001 from baseline).. Nasal challenge with ASA affects significantly both nasal VOL and Req, and LTE4 excretion in all ASA-intolerant subjects. During the nasal challenge, severity of respiratory reactions proves associated with the highest basal LTE4 synthesis. This feature reflects a spectrum of respiratory tract reactions where cysteinil-LTs can play a specific diagnostic role.

Topics: Adult; Aspirin; Asthma; Bronchial Hyperreactivity; Cysteine; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Leukotrienes; Lysine; Male; Middle Aged; Nasal Cavity; Nasal Provocation Tests; Rhinometry, Acoustic

Chronic airway inflammation is a feature of asthma. Increased levels of cysteinyl leukotrienes (cys-LTs; leukotriene [LT]C(4), LTD(4), LTE(4)) have been shown in the exhaled breath condensate (EBC) of children with moderate-to-severe asthma. The aim of this study was to examine the relationship between EBC cys-LTs (LTE(4)) levels and bronchial hyperreactivity in children with mild asthma in order to evaluate the clinical utility of measuring EBC cys-LTs levels.. We measured LTE(4) levels in the EBC of children aged 8 to 18 years, including healthy nonasthmatic children (n = 6) and children with mild asthma (n = 37). Patients with mild asthma were classified into the following three groups: group 1, participants who had been asymptomatic (no wheezing/symptoms of asthma) for > 6 months prior to examination (n = 12); group 2, participants who were asymptomatic but had had wheezing/symptoms of asthma within 6 months before examination (n = 18); and group 3, patients with current wheeze and/or mild symptoms of asthma exacerbation at the time of examination.. Exhaled LTE(4) levels were increased in all children with mild asthma compared with nonasthmatic control subjects (5.69 +/- 9.62 pg/20 min vs 0.74 +/- 0.79 pg/20 min, p < 0.05) [mean +/- SD]. In particular, the EBC LTE(4) levels in group 2 (4.99 +/- 6.70 pg/20 min) and group 3 (14.66 +/- 17.11 pg/20 min) were increased compared with control subjects and group 1 (1.50 +/- 1.69 pg/20 min). The EBC LTE(4) levels negatively correlated with the provocative concentration of methacholine causing a 15% fall in FEV(1) (r = - 0.454, p = 0.012).. EBC cys-LTs may be useful as a noninvasive marker assessing airway inflammation and hyperreactivity in children with asthma.

Topics: Adolescent; Asthma; Biomarkers; Breath Tests; Bronchial Hyperreactivity; Bronchial Provocation Tests; Child; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Methacholine Chloride; Reference Values; Statistics as Topic

The inflammatory mechanisms of hypertonic saline-induced bronchoconstriction are not well understood.. Seventeen asthmatics with (n=11) and without bronchial hyperresponsiveness (BHR) (n=6) and 18 randomly selected nonatopic nonasthmatic controls without BHR were evaluated by urine samples collected before and 1 h after hypertonic saline provocation test. Histamine, 11beta-PGF2alpha, and LTE4 were analysed by enzyme immunoassay (EIA) and eosinophil protein X (EPX) by radioimmunoassay (RIA).. The levels of leukotriene E4 (LTE4) increased significantly after the challenge tests, both in the asthmatics (median: 354 pg/mg pre-challenge vs. 628 pg/mg post-challenge; P=0.05) and in the controls (median: 294 pg/mg pre-challenge vs. 460 pg/mg post-challenge; P <0.01). The levels of histamine also increased significantly in the latter (median: 299 micromol/mg pre-challenge vs. 569 micromol/mg post-challenge; P=0.03). However, the levels of 11beta-PGF2alpha and EPX did not change significantly after the challenge tests either in the asthmatics or in the controls.. The inhalation of hypertonic saline increased urinary excretion of LTE4 both in the asthmatics and in the controls. The slight increase of leukotrienes was enough to induce airway obstruction in some of the asthmatics, because of the hyperresponsiveness in their airways.

Topics: Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Case-Control Studies; Child; Female; Histamine; Humans; Inflammation Mediators; Leukotriene E4; Male; Saline Solution, Hypertonic

It is still uncertain how viral respiratory infections cause acute exacerbations of bronchial asthma, although several mechanisms have been proposed. We studied the relationship between the airway narrowing and the inflammatory and bronchospastic factors in peripheral venous blood and urine, in 30 patients with asthma at the exacerbations caused by upper respiratory tract infections (URTIs). Acute exacerbations caused decreases in peak expiratory flow rate (PEFR) in all 30 patients with asthma. Asthma exacerbations caused the rises in serum levels of interleukin-6, soluble intercellular adhesion molecule-1 and eosinophil cationic protein, concentrations of urinary leukotriene E4 and plasma histamine, compared with those in patients with asthma at a stable condition and those in 30 control subjects (p < 0.05). The values of PEFR at the exacerbations correlated with the levels of these factors. Treatment with oral glucocorticoids reversed the decreases in PEFR and the increases in these factors. At the onset of URTIs, rhinovirus and influenza type A virus were identified in 13 and 7 patients, respectively. Each of parainfluenza virus, adenovirus, and enterovirus was identified in one patient. These findings suggest that respiratory viral infections may cause acute asthma exacerbations via the production of mediators that induce inflammation and bronchospasm.

Topics: Acute Disease; Asthma; Bronchial Hyperreactivity; Eosinophil Cationic Protein; Female; Glucocorticoids; Histamine; Humans; Influenza A virus; Intercellular Adhesion Molecule-1; Interleukin-6; Leukotriene E4; Male; Middle Aged; Peak Expiratory Flow Rate; Respiratory Tract Infections; Retrospective Studies; Rhinovirus; Time Factors

Evidence suggests that small airways contribute to clinically significant processes in asthma. Cysteinyl leukotrienes (CysLTs) are considered to be pivotal mediators in the pathogenesis of asthma. Montelukast (MK), a specific CysLT1 receptor antagonist, is metabolized in two main hydroxylated metabolites (termed M5 and M6, respectively).. The aims of this study were to compare the responsiveness of small and large human bronchi to the three CysLTs, to evaluate the antagonist activity of MK, M5 and M6 in these preparations of human bronchi, and to characterize the CysLT receptors involved in the contractile response.. In isolated small bronchus (i.d. 0.5-2 mm), the potencies (-log molar EC50) of LTC4, LTD4 and LTE4 were 9.3 (n=11), 9.1 (n=30) and 8.4 (n=14), respectively. The three CysLTs were about 30-fold more potent in small bronchi than in larger bronchi (i.d. 4-6 mm). In small bronchi, MK significantly shifted to the right the CysLT concentration-effect curves with pA2 values against LTC4, LTD4 and LTE4 of 9.1 (n=3), 9.0 (n=11) and 8.7 (n=5), respectively. The antagonist potencies of M6 and M5 were similar to MK and fivefold lower, respectively. A similar activity of MK against the three CysLTs suggested that CysLT1 receptors are involved in the contraction of human bronchus. Analysis by RT-PCR also indicated that human bronchus mainly expressed CysLT1 receptors.. MK exerts a potent antagonist activity against the particularly potent constricting effects of CysLTs in isolated human small bronchi, which only expressed the CysLT1 receptor subtype. The metabolites of MK are also potent in vitro antagonists, but may not participate in the therapeutic activity of MK due to their low plasma concentrations in patients treated with the recommended dose of MK.

Topics: Acetates; Adult; Aged; Aged, 80 and over; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cyclopropanes; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Male; Middle Aged; Quinolines; Reverse Transcriptase Polymerase Chain Reaction; Sulfides

Inhalation of heparin attenuates hyperventilation-induced bronchoconstriction in humans and dogs. The purpose of this study was to determine whether heparin inhibits the late-phase response to hyperventilation, which is characterized by increased peripheral airway resistance (RP), eicosanoid mediator production, neutrophilic/ eosinophilic inflammation, and airway hyperreactivity (AHR) at 5 h after dry air challenge (DAC). Fiberoptic bronchoscopy was used to record RP and airway reactivity (DeltaRP) to aerosol and intravenous histamine before and 5 h after DAC. Bronchoalveolar lavage fluid (BALF) cells and eicosanoid mediators were also measured approximately 5 h after DAC. DAC of vehicle-treated bronchi resulted in late-phase airway obstruction (approximately 120% increase over baseline RP), inflammation, increased BALF concentrations of leukotriene (LT) C(4), LTD(4), and LTE(4) and prostaglandin (PG)D(2), and AHR. Pretreatment with aerosolized heparin attenuated late-phase airway obstruction by approximately 50%, inhibited eosinophil infiltration, reduced BALF concentrations of LTC(4), LTD(4), and LTE(4) and PGD(2), and abolished AHR. We conclude that heparin inhibits hyperventilation-induced late-phase changes in peripheral airway function, and does so in part via the inhibition of eosinophil migration and eicosanoid mediator production and release.

Topics: Administration, Inhalation; Airway Resistance; Animals; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Bronchoscopy; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Eicosanoids; Eosinophils; Heparin; Humans; Hyperventilation; Inflammation; Leukotriene C4; Leukotriene D4; Leukotriene E4; Male; Neutrophils; Prostaglandin D2; Time Factors

During or after surgery, asthma attacks due to airway hyperresponsiveness (AHR) are likely to occur in patients with bronchial asthma. Preoperative administration of corticosteroid for prevention of perioperative asthma attacks is useful. We examined the mechanism of prevention of perioperative asthma attacks by the preoperative administration of corticosteroid in vitro.. Five patients with asthma were treated with 20 mg of prednisolone orally for 2 preoperative days and 80 mg of methylprednisolone IV immediately before and after surgery. In another five patients without asthma, no steroids were administered. A noncarcinomatous part of the resected tissue from each patient with lung cancer was passively sensitized with the serum of an atopic patient. In the patients without asthma, the tissue was treated with or without dexamethasone, and then mite antigen was added.. The culture supernatant and lung tissue were recovered, and the supernatant was assayed for histamine, leukotriene E(4) (LTE(4)), interleukin (IL)-5, and tumor necrosis factor (TNF)-alpha. Degranulation of mast cells was measured by tryptase staining of the lung tissue, and the expression of messenger RNA (mRNA) of IL-5 and TNF-alpha was determined by the reverse transcriptase-polymerase chain reaction method.. While preoperative administration of corticosteroid did not suppress the release of histamine and LTE(4) from the lungs of asthmatic patients, it completely suppressed IL-5 and TNF-alpha production at the mRNA level. The same results were obtained in lung tissues of nonasthmatic patients treated in vitro with dexamethasone.. Our results suggest that corticosteroid treatment reduces AHR and prevents perioperative attacks of asthma primarily by suppressing the production of inflammatory cytokines.

Topics: Administration, Oral; Adult; Aged; Asthma; Bronchial Hyperreactivity; Cytokines; Female; Gene Expression; Histamine Release; Humans; Infusions, Intravenous; Interleukin-5; Intraoperative Complications; Leukotriene E4; Lung; Lung Neoplasms; Male; Methylprednisolone; Middle Aged; Pneumonectomy; Prednisolone; Premedication; Pulmonary Emphysema; RNA, Messenger; Tumor Necrosis Factor-alpha

Several studies have confirmed the presence of animal dander allergens in school dust but the effect of this indirect animal exposure on health has not been evaluated. In this study we investigated bronchial reactivity and markers of eosinophil activity and inflammation during two separate weeks of school in 10 children with mild asthma and a positive skin prick test to cat and dog. At the beginning and the end of the first week the children underwent bronchial challenges with methacholine, and at the beginning and the end of the second week they underwent nasal lavages (NAL) and induced sputum samplings. Blood and urine samples for analysis of inflammatory markers were obtained before and after both school weeks. Peak expiratory flow (PEF) and symptoms of asthma and allergy were recorded daily, and spirometry was performed on each visit. The exposure to animal dander allergens was estimated from dust samples obtained in the subjects' schools and homes. Bronchial sensitivity to methacholine increased in the week when this was measured. The proportion of eosinophils in peripheral blood, and urinary eosinophil protein X (EPX), decreased in both weeks. There was a trend towards an increase of eosinophil peroxidase (EPO) and myeloperoxidase (MPO) in sputum in the week when these proteins were measured. The concentrations of cat (Fel d1) and dog (Can f1) allergens were higher in dust collected in schools than in homes. Our results show that in children with mild asthma and animal dander allergy, there is a significantly increased bronchial sensitivity to methacholine after one school week. There is also a significant decrease in the number of circulating eosinophils and a trend towards an increase of sputum EPO, which could correlate with the early phase of eosinophil recruitment to the lungs. These effects may be related to the continuous exposure to animal allergens in school dust.

Topics: Adolescent; Allergens; Animals; Antigens, Plant; Asthma; Biomarkers; Blood Proteins; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Cats; Child; Dogs; Dust; Eosinophil Peroxidase; Eosinophil-Derived Neurotoxin; Eosinophils; Female; Glycoproteins; Humans; Leukotriene E4; Male; Methacholine Chloride; Nasal Lavage Fluid; Peroxidase; Peroxidases; Ribonucleases; Sputum

A random population-based sample of 131 subjects was used to assess the value of serum eosinophil cationic protein (ECP), serum myeloperioxidase (MPO), and urinary leukotriene E4 (LTE4) in predicting bronchial hyper-responsiveness measured by methacholine challenge. Special interest was focused on the history of aspirin intolerance and on smoking as contributing factors. The mean serum ECP and MPO were higher in hyper-reactive [provocational dose causing a 20% fall in forced expiratory volume in 1 sec. (PD20) < or = 6900 micrograms] than in non-hyper-reactive subjects (22.3 vs. 13.2 micrograms l-1, P < 0.001 and 377 vs. 278 micrograms l-1, P = 0.001, respectively). This was also seen in current smokers vs. never smokers (17.2 vs. 12.9 micrograms l-1, P = 0.03 and 372 vs. 286 micrograms l-1, P = 0.04, respectively). There were no differences in baseline urinary excretion of LTE4 between hyper-reactive and non-hyper-reactive subjects. During the 2 h after methacholine challenge, urinary LTE4 excretion increased from 53.8 and 69.0 ng mmol-1 creatinine in non-hyper-reactive subjects, but there was no change in hyper-reactive subjects (non-hyper-reactive vs. hyper-reactive, P = 0.06). The increase was greatest in subjects with aspirin intolerance causing urticaria or angioedema but not aggravation of asthma (from 58.5 to 87.2 ng mmol-1 creatinine), probably due to extrapulmonary leukotriene production. Our results indicate that serum ECP and MPO, but not urinary LTE4 (even in subjects with a history of aspirin intolerance), predict bronchial hyper-responsiveness to methacholine. The subject's smoking history must be taken into account when these parameters are considered.

Topics: Adult; Aged; Aspirin; Biomarkers; Blood Proteins; Bronchial Hyperreactivity; Bronchoconstrictor Agents; Eosinophil Granule Proteins; Eosinophils; Female; Humans; Leukotriene E4; Male; Methacholine Chloride; Middle Aged; Peroxidase; Ribonucleases; Smoking

We examined whether lipid mediators have a causal role in neonatal hyperoxia-induced lung damage, specifically, airway remodeling and hyperresponsiveness. Newborn rat pups were exposed to hyperoxia (> 95% O2 from Days 4 to 14 and 65% from Days 14 to 32) or normoxia. The 5-lipoxygenase inhibitor, LTD4 receptor antagonist, and inhibitor of platelet-activating factor synthesis, Wy-50,295 (30 mg/kg), or vehicle was administered daily from Days 3 to 32. Oxygen exposure significantly increased (p < 0.05) the production of one potential lipid mediator group, peptido-LTs, from explanted lung slices and large airways from 2-wk-old rat pups. At 4 wk, only the large airway tissue output showed significant elevation because of oxygen exposure. At both ages, Wy-50,295 significantly decreased (p < 0.05) the production of peptido-LTs in the lung and large airways of oxygen-exposed pups. Pulmonary function and airway wall morphometry were studied in 5-wk-old rat pups 2 to 3 d after oxygen exposure and drug administration ceased. The resistance change in response to methacholine (0 to 20 microg/kg body weight given intravenously) was greater (p < 0.02) in oxygen-exposed animals. Oxygen exposure caused significant (60% increase) smooth muscle thickening (p < 0.05). Wy-50,295 prevented the oxygen-induced airway hyperresponsiveness and smooth muscle thickening. We conclude that chronic hyperoxic exposure causes an increase in pulmonary production of at least one lipid mediator, peptido-LTs, from newborn rats and that this is associated with airway smooth muscle layer thickening and, consequently, airway hyperresponsiveness.

Topics: Animals; Animals, Newborn; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchopulmonary Dysplasia; Humans; Infant, Newborn; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lipoxygenase Inhibitors; Muscle, Smooth; Naphthaleneacetic Acids; Oxygen; Quinolines; Rats; Rats, Sprague-Dawley

We used the 5-lipoxygenase-activating protein (FLAP) antagonist MK-0591 to investigate the importance of leukotrienes (LT) in causing ozone-induced bronchoconstriction, airway inflammation, and airway hyperresponsiveness in dogs. Six random source dogs were studied. On one day, dogs were treated with MK-0591 (2 mg/kg iv) followed by a continuous intravenous infusion of 8 micrograms.kg-1.min-1. On the other day, the diluent was infused. Acetylcholine airway responsiveness was measured before and 1 h after ozone inhalation (3 ppm for 30 min). On each day, whole blood and bronchoalveolar lavage (BAL) cells were challenged with calcium ionophore to stimulate LTB4 production. Urinary LTE4 levels were measured before and after ozone. MK-0591 inhibited LTB4 production in whole blood by 96% (P = 0.001) and that from BAL cells by 91% (P = 0.001). By contrast, MK-0591 had no effect on ozone-induced bronchoconstriction, airway hyperresponsiveness, or influx of neutrophils into BAL. The mean log difference of the pre- to post-acetylcholine provocative concentration was 0.64 +/- 0.40 during MK-0591 treatment and 0.68 +/- 0.40 during diluent treatment (P = 0.71). These results indicate that peptidoleukotrienes are produced during ozone inhalation and that MK-0591 inhibits LT production in dogs. However, LTs do not play a role in ozone-induced bronchoconstriction, airway inflammation, or airway hyperresponsiveness in dogs.

Topics: 5-Lipoxygenase-Activating Proteins; Acetylcholine; Airway Resistance; Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Carrier Proteins; Dogs; Indoles; Inflammation; Leukotriene Antagonists; Leukotriene B4; Leukotriene E4; Leukotrienes; Lipoxygenase Inhibitors; Membrane Proteins; Ozone; Quinolines; Respiratory System

No single mediator is responsible for the clinical and pathological events in bronchial asthma. Nevertheless, there is now substantial evidence that the sulphidopeptide leukotrienes play an important role in the pathophysiology of the disease. They are potent in eliciting bronchoconstriction, mucus production and vasodilatation, and may enhance the airways hyperresponsiveness that is characteristic of the disease. The sulphidopeptide leukotrienes are present in the airways of asthmatic patients and their release has been demonstrated in acute severe asthma. They are released during asthmatic attacks provoked by a range of stimuli. The evidence from studies using sulphidopeptide leukotriene antagonists and 5-LO inhibitors suggests strongly that sulphidopeptide leukotrienes contribute to the resting asthmatic airways tone and to the asthmatic responses elicited by exercise, allergen, aspirin and cold, dry air challenges. These mediators may also contribute to the airways hyperresponsiveness induced by allergen challenge of sensitized subjects. Preliminary results indicate that the administration of leukotriene receptor antagonists and 5-LO inhibitors may benefit patients with chronic asthma. Further studies are now needed to define better the role of these novel drugs in the management of the disease.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Guinea Pigs; Humans; Leukotriene E4; Receptors, Immunologic; Receptors, Leukotriene; SRS-A

Leukotriene E4 (LTE4) is excreted into the urine in a relatively constant proportion of 4-7% when either leukotriene C4 (LTC4) or LTE4 is intravenously infused, regardless of the magnitude of the infused dose. Measurement of LTE4 in urine is, therefore, a convenient and non-invasive method for assessing changes in the rate of total body sulphidopeptide leukotriene production. We assayed urinary LTE4 in 17 normal subjects, 31 subjects with asthma without aspirin sensitivity, and 10 aspirin-sensitive subjects. The relationship between urinary LTE4 and nonspecific bronchial hyperresponsiveness, as assessed by the provocative dose producing a 20% fall in forced expiratory volume in one second (PD20) to inhaled histamine, was examined in 19 non-aspirin-sensitive asthmatic subjects. The urinary LTE4 values were log-normally distributed. Urinary LTE4 was detected in 28 of the 31 non-aspirin-sensitive asthmatic subjects, and the geometric mean (95% confidence interval (CI) of 43 (32-57) pg.mg-1 creatinine was no different to that of 34 (25-48) pg.mg-1 creatinine measured in the normal subjects. The geometric mean of 101 (55-186) pg.mg-1 creatinine measured in the aspirin-sensitive asthmatics was significantly higher than that measured in the normal subjects (p less than 0.005) and in the asthmatic subjects who were non-aspirin-sensitive (p less than 0.002), but there was considerable overlap between the three groups. There was no relationship between urinary LTE4 and PD20, or between urinary LTE4 and baseline forced expiratory volume in one second (FEV1) (% predicted). Thus, measurement of LTE4 in a single sample of urine will not predict the extent of bronchial hyperresponsiveness or degree of airflow obstruction.

Topics: Adult; Aspirin; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Drug Hypersensitivity; Female; Histamine; Humans; Leukotriene E4; Male; SRS-A

Leukotriene (LT) D4 receptor in the granulation tissue formed in the air pouch-type allergic inflammation model in rats was analyzed. Membrane preparation of the granulation tissue obtained 3-9 days after the antigen challenge has specific binding sites of [3H]LTD4. Scatchard analysis showed that the affinity (Kd) and the density (Bmax) were not changed among the granulation tissue obtained 3-9 days after the antigen challenge. The Kd value in the granulation tissue (0.90 +/- 0.12 nM) was close to that in the rat lung (1.00 +/- 0.24 nM) and the guinea pig lung (0.86 nM). On the other hand, Bmax (62 +/- 8 fmol/mg protein) in the granulation tissue was higher than that in the rat lung (21 +/- 4 fmol/mg protein) but was far less than that in the guinea pig lung (405 fmol/mg protein). LTC4 and LTE4 inhibited the binding of [3H]LTD4 to the membrane preparation of the granulation tissue in a concentration-dependent manner. IC50 of LTC4 and LTE4 were 1 x 10(-7) and 2 x 10(-7) M, respectively. A guanine nucleotide, guanyl-5'-yl-imido-diphosphate (GppNHp), reduced [3H]LTD4 binding to the membrane preparation of the granulation tissue suggesting that LTD4 receptors in the granulation tissue are associated with G proteins. These results indicate that LTD4 binding sites in the granulation tissue are high affinity receptors for LTD4. A possible role of LTD4 in the recurrence of allergic inflammation in the chronic phase is discussed.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchitis; Cell Membrane; Disease Models, Animal; Granulation Tissue; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Leukotriene E4; Male; Rats; Rats, Sprague-Dawley; Receptors, Immunologic; Receptors, Leukotriene; Specific Pathogen-Free Organisms; SRS-A