leukotriene-e4 and Airway-Obstruction

We have shown that inhalation of leukotriene (LT) E 4 contributes to specific recruitment of eosinophils to the airway mucosa in patients with asthma at the time of maximal decrease in airway-specific conductance.. We examined the ability of the cysteinyl LT 1 receptor antagonist, zafirlukast, to improve or prevent LT-mediated eosinophilia and airway obstruction in asthma.. Bronchial biopsies were taken and pulmonary function was measured before and 4 to 6 hours after the dose of inhaled LTE 4 causing a > or =15% fall in FEV 1 at baseline both at week 0 and after 6-week randomly assigned treatment with a high dose of zafirlukast, 80 mg twice daily.. Leukotriene E 4 inhalation at week 0 doubled the number of eosinophils in the airway mucosa in 21 of 25 patients with mild asthma, increased the numbers of neutrophils and lymphocytes, and decreased FEV 1 (-17%). Zafirlukast reduced both airway eosinophilia and obstruction in FEV 1 , whereas with a double-blind placebo treatment, the effect of LTE 4 on both parameters persisted for 6 weeks. On repeat LTE 4 inhalation challenge after 6 weeks, zafirlukast treatment prevented further airway eosinophilia and decrease in FEV 1 seen in the placebo group.. Persistent LTE 4 -induced airway eosinophilia may form the basis of an amplification mechanism for further eosinophil recruitment. Zafirlukast prevents LTE 4 -induced eosinophilic airway inflammation in mild asthma.

Topics: Administration, Inhalation; Adult; Airway Obstruction; Anti-Asthmatic Agents; Asthma; Bronchial Provocation Tests; Double-Blind Method; Eosinophilia; Female; Forced Expiratory Volume; Humans; Indoles; Leukotriene Antagonists; Leukotriene E4; Lung; Male; Middle Aged; Phenylcarbamates; Sulfonamides; Tosyl Compounds

Aspirin-exacerbated respiratory disease (AERD) is recognized as a distinct asthma phenotype. It usually has a severe course accompanied by chronic hyperplastic eosinophilic sinusitis with nasal polyps, blood eosinophilia, and increased concentrations of urinary leukotriene E4 (LTE4). More insightful analysis of individual patients shows this group to be nonhomogeneous.. We sought to identify any likely subphenotypes in a cohort of patients with AERD through the application of latent class analysis (LCA).. Clinical data from 201 patients with AERD (134 women) were collected from questionnaires. Standard spirometry, atopy traits, blood eosinophilia, and urinary LTE4 concentrations were evaluated. LCA was applied to identify possible AERD subphenotypes.. Four classes (subphenotypes) within the AERD phenotype were identified as follows: class 1, asthma with a moderate course, intensive upper airway symptoms, and blood eosinophilia (18.9% of patients); class 2, asthma with a mild course, relatively well controlled, and with low health care use (34.8% of patients); class 3, asthma with a severe course, poorly controlled, and with severe exacerbations and airway obstruction (41.3% of patients); and class 4, poorly controlled asthma with frequent and severe exacerbations in female subjects (5.0% of patients). Atopic status did not affect class membership. Patients with particularly intensive upper airway symptoms had the highest levels of blood eosinophilia and the highest concentrations of urinary LTE4.. LCA revealed unique AERD subphenotypes, thus corroborating the heterogeneity of this population. Such discrimination might facilitate more individualized treatment in difficult-to-treat patients.

Topics: Adult; Airway Obstruction; Asthma, Aspirin-Induced; Cell Movement; Eosinophils; Female; Humans; Leukotriene E4; Male; Middle Aged; Nasal Polyps; Sinusitis; Spirometry; Statistics as Topic

Use of leukotriene receptor antagonists improves disease control in children and adults with asthma. However, the relationship between cysteinyl leukotriene levels and indices of daily asthma control has not been studied directly.. We sought to assess the relationship between daily variability in urinary leukotriene E(4) (LTE(4)) levels and daily lung function in children primarily taking inhaled corticosteroids (ICSs) and long-acting beta-agonists (LABAs).. Fifty children primarily with moderate-to-severe asthma were followed with measurements of urinary LTE(4), monitoring of FEV(1), and albuterol use.. Increasing urinary LTE(4) levels were associated with significant (P = .006) decreases in percent predicted FEV(1) (ppFEV(1)) averaging 4.7% per interquartile range increase in LTE(4) and accompanied by increased albuterol use (P = .03). Children with lower FEV(1)/forced vital capacity ratios demonstrated larger LTE(4)-related FEV(1) decreases (6.4%) compared to those with higher ratios (4.2%, P = .009). This association was blunted in children taking montelukast (1.4% ppFEV(1) decrease) compared with that in children not taking this medication (5.4% ppFEV(1) decrease, P = .05). Children with lower lung function ratios demonstrated greater blunting of the LTE(4) effect with montelukast (0.9% ppFEV(1) decrease) compared to those with higher ratios (3.6% ppFEV(1), P = .0002).. Daily variability in LTE(4) levels is associated with clinically significant decreases in pulmonary function. In children who demonstrate a response associated with an increase in urinary LTE(4) levels, leukotriene receptor antagonists protect against daily FEV(1) decreases. This protection might be greatest in those with persistent airway obstruction despite use of ICS and LABA therapy.. Therapies designed to block cysteinyl leukotriene production or function might benefit children receiving ICS and LABA therapy who continue to experience persistent disease.

Topics: Acetates; Adolescent; Airway Obstruction; Albuterol; Asthma; Child; Chronic Disease; Cyclopropanes; Disease Susceptibility; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Quinolines; Severity of Illness Index; Sulfides

Cysteinyl-leukotrienes have been reported to have a primary role in the induction of nasal blockage of allergic rhinitis. However, there has been little experimental evidence that substantiates the relationship between nasal blockage severity and urinary leukotriene E4 (U-LTE4) concentration in patients with seasonal allergic rhinitis (SAR).. The concentrations of urinary mediators in 20 SAR patients were measured using an enzyme immunoassay to determine the relationship between nasal blockage severity and U-LTE4 concentration in patients with SAR.. The basal U-LTE4 concentration was significantly higher in SAR patients with severe nasal blockage than in those with mild nasal blockage and in healthy control subjects. Although U-LTE4 concentrationwas significantly higher in patients with both asthma and SAR than in SAR patients with mild nasal blockage, no significant difference in the U-LTE4 concentration between patients with both asthma and SAR and SAR patients with severe nasal blockage was found. There was a significant correlation between U-LTE4 and urinary 9alpha11beta-prostoglandin F2 (9alpha11betaPGF2) concentrations (rs = 0.51, P = 0.02) in SAR patients.. Although specific sites and cells of cysteinyl-leukotriene biosynthesis could not be determined in this study, severe nasal blockage is associated with the increased excretion level of U-LTE4.

Topics: Adolescent; Adult; Airway Obstruction; Case-Control Studies; Dinoprost; Eosinophil-Derived Neurotoxin; Female; Humans; Immunoenzyme Techniques; Leukotriene E4; Male; Middle Aged; Nasal Cavity; Osmolar Concentration; Rhinitis, Allergic, Seasonal; Ribonucleases; Severity of Illness Index

Previous studies have indicated that increased dietary salt consumption worsens postexercise pulmonary function in humans with exercise-induced asthma (EIA). It has been suggested that EIA and hyperpnea-induced airway obstruction (HIAO) in guinea pigs (an animal model of EIA) are mediated by similar mechanisms. Therefore, the purpose of this study was to determine whether altering dietary salt consumption also exacerbated HIAO in guinea pigs. Furthermore, the potential pathway of action of dietary salt was investigated by blocking leukotriene (LT) production during HIAO in guinea pigs. Thirty-two male Hartley strain guinea pigs were split into two groups. One group (n = 16) of animals ingested a normal-salt diet (NSD) for 2 wk; the other group (n = 16) ingested a high-salt diet (HSD) for 2 wk. Thereafter, animals were anesthetized, cannulated, tracheotomized, and mechanically ventilated during a baseline period and during two dry gas hyperpnea challenges. After the first challenge, the animals were administered either saline or nordihydroguaiaretic acid, a LT inhibitor. Bladder urine was analyzed for electrolyte concentrations and urinary LTE(4). The HSD elicited higher airway inspiratory pressures (Ptr) than the NSD (P < 0.001) postchallenge. However, after infusion of the LT inhibitor and a second hyperpnea challenge, HIAO was blocked in both diet groups (P < 0.001). Nonetheless, the HSD group continued to demonstrate slightly higher Ptr than the NSD group (P < 0.05). Urinary LTE(4) excretion significantly increased in the HSD group compared with the NSD group within treatment groups. This study has demonstrated that dietary salt loading exacerbated the development of HIAO in guinea pigs and that LT release was involved in HIAO and may be moderated by changes in dietary salt loading.

Topics: Airway Obstruction; Animals; Body Weight; Bronchoconstriction; Eating; Electrolytes; Guinea Pigs; Hyperventilation; Leukotriene E4; Lipoxygenase Inhibitors; Male; Masoprocol; Physical Exertion; Sodium Chloride; Sodium Chloride, Dietary

1. In this study, an attempt was made to distinguish between local and systemic effects of low doses of the topical glucocorticoid, budesonide. The effect of aerosolized budesonide administered to the lower airways versus intravenously administered budesonide on the acute and late response to nebulized Ascaris suum extract in the lung, was evaluated in the minipig after active sensitization with purified A. suum antigen. Budesonide was administered once, 1 h prior to A. suum challenge and airway reactions and mediator release were observed for 8 h after allergen challenge. 2. In the budesonide aerosol group (n = 6), 10.2 +/- 1.2 micrograms kg-1 budesonide was given locally and in the budesonide infusion group (n = 5), 5 micrograms kg-1 was given intravenously. The area under the plasma concentration curve for budesonide during the experiment was 11.4 +/- 1.2 and 10.3 +/- 1.2 nM h in the budesonide aerosol and budesonide infusion group, respectively (no significant difference). The lung tissue content of budesonide in the two groups was 45.2 +/- 4.9 and 18.4 +/- 3.5 nmol kg-1 dry tissue, respectively, 8 h after allergen challenge (P < 0.05). For comparison, 6 pigs were given budesonide vehicle as an infusion prior to A. suum challenge. 3. Total lung resistance (RL) increased acutely (maximal response within 15 min) in the budesonide aerosol, budesonide infusion and budesonide vehicle groups (by 91 +/- 40, 150 +/- 86 and 80 +/- 27%, respectively). The acute reaction partially resolved at about 1 h and was followed by a late increase in RL in the budesonide infusion and budesonide vehicle groups (by 251 +/- 148 and 281 +/- 136% at 8 h, respectively). However, no late change in RL was seen in the budesonide aerosol group (7 +/- 24%). 4. Aerosolized budesonide had a protective effect in that it attenuated the late changes in arterial blood gas and pH as well as the late elevation of plasma catecholamines. Budesonide given as an infusion did not protect against the late changes in these parameters. However, budesonide aerosol or infusion did not inhibit the late vasodilation in the bronchial circulation. 5. Histamine and cysteinyl-leukotrienes were released during the acute reaction as measured by urinary concentration of methylhistamine and leukotriene E4 respectively. There was no release of histamine during the late reaction. A late increase in leukotriene E4 was observed in 2 of the budesonide infusion and 3 of the budesonide vehicle pigs, whereas no such i

Topics: Administration, Inhalation; Administration, Topical; Airway Obstruction; Allergens; Analysis of Variance; Animals; Anti-Inflammatory Agents; Antigens, Helminth; Ascaris suum; Blood Pressure; Budesonide; Glucocorticoids; Heart Rate; Histamine; Injections, Intravenous; Leukotriene E4; Lung; Male; Pregnenediones; Swine; Swine, Miniature; Vascular Resistance

The pathophysiology of chronic lung disease (CLD) in premature infants who require mechanical ventilation and prolonged oxygen supplementation has been well-described but the underlying mechanisms are not understood. Our aim was to test the hypothesis that excess cysteinyl leukotriene (LT) production was a contributing factor in CLD. We compared LT production and lung function, at 7 months of age, in nine premature infants with CLD and in eight control infants without CLD. None of the control infants developed any neonatal respiratory problems, but two subsequently required bronchodilator therapy. Respiratory function was assessed by the measurement of thoracic gas volume (TGV), airways resistance (Raw) and functional residual capacity (FRC). Total cysteinyl LT production was quantified by measurement of leukotriene E4 (LTE4) in a spot urine sample. Although all patients were asymptomatic at follow-up, there was evidence of significant lung function abnormalities in infants with CLD. The CLD infants had significantly elevated TGV, Raw and FRC values reflecting airway obstruction when compared to the controls. Urinary LTE4 levels were significantly higher in the CLD infants when compared to the controls (geometric mean: 741 and 337 pmol.mmol-1 creatinine, respectively). There was no direct correlation between urinary LTE4 levels in the CLD group and TGV, Raw or FRC values. Although this study is small and a direct correlation between lung function and urinary leukotriene E4 was not demonstrated, pathological lung function and an enhanced urinary leukotriene E4 production in infants with chronic lung disease would tend to suggest that the cysteinyl leukotrienes were involved in the sequelae of this disease.

Topics: Airway Obstruction; Airway Resistance; Bronchodilator Agents; Chronic Disease; Cohort Studies; Creatinine; Follow-Up Studies; Functional Residual Capacity; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Leukotriene E4; Lung; Lung Diseases; Oxygen Inhalation Therapy; Prospective Studies; Respiration, Artificial; Tidal Volume

Topics: Airway Obstruction; Asthma; Bronchoconstriction; Humans; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Leukotriene E4; Leukotrienes

Topics: Airway Obstruction; Asthma; Bronchi; Bronchial Provocation Tests; Forced Expiratory Volume; Histamine; Humans; Leukotriene E4; Muscle Contraction; Muscle, Smooth; SRS-A

Upon a specific allergic reaction mediators released from mast cells found free in the bronchial lumen or in the epithelial surface loosen the interepithelial cell tight-junctions allowing the entrance of more allergen to deeper mast cells. The primary and secondary mediators thereby generated induce further increased vascular permeability which leads to the entrance of plasma proteins and platelets. The other immediate responses induced by mediator release are smooth muscle constriction, mucus secretion and leukocyte chemoattraction. Vagal afferent and reflex efferent stimulation are induced by histamine and probably other mediators which might contribute both to the bronchospasm as well as mucous gland secretion. Subacute responses include increased cellular infiltrates, mucosal edema, desquamation, basement membrane thickening, goblet cell hyperplasia and mucus secretion. These responses may occur because of the continued release of primary and secondary mediators as well as effects caused by the mast cell granule matrix-derived factors. It can thus be seen that many of the pathologic features of asthma may be attributed to mast cell degranulation.

Topics: Airway Obstruction; Asthma; Bradykinin; Capillary Permeability; Histamine; Humans; Leukotriene E4; Mast Cells; Mucus; Muscle Contraction; Muscle, Smooth; Prostaglandins; SRS-A; Thromboxane A2