leukotriene-e4 and Rhinitis--Allergic--Seasonal

Cysteinyl-leukotrienes (cysteinyl-LTs), that is, LTC4, LTD4, and LTE4, trigger contractile and inflammatory responses through the specific interaction with G protein-coupled receptors (GPCRs) belonging to the purine receptor cluster of the rhodopsin family, and identified as CysLT receptors (CysLTRs). Cysteinyl-LTs have a clear role in pathophysiological conditions such as asthma and allergic rhinitis (AR), and have been implicated in other inflammatory conditions including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. Molecular cloning of human CysLT1R and CysLT2R subtypes has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Interestingly, recent data provide evidence for the immunomodulation of CysLTR expression, the existence of additional receptor subtypes, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Furthermore, genetic variants have been identified for the CysLTRs that may interact to confer risk for atopy. Finally, a crosstalk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize and attempt to integrate recent data derived from studies on the molecular pharmacology and pharmacogenetics of CysLTRs, and will consider the therapeutic opportunities arising from the new roles suggested for cysteinyl-LTs and their receptors.

Topics: Adult; Animals; Asthma; Cardiovascular Diseases; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Hydroxyurea; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Membrane Proteins; Pharmacogenetics; Receptors, Leukotriene; Receptors, Purinergic; Recombinant Proteins; Rhinitis, Allergic, Seasonal; SRS-A; Tissue Distribution

Cysteinyl leukotrienes (CysLTs: LTC4, LTD4, and LTE4) are a family of potent inflammatory mediators that appear to contribute to the pathophysiologic features of allergic rhinitis. Because treatment with a CysLT1 receptor antagonist and a 5-lipoxygenase inhibitor modified allergen-induced nasal blockage in patients with allergic rhinitis, and CysLTs were detected in nasal cavity lavage fluid, it has been suggested that CysLTs act as significant inflammatory mediators in allergic rhinitis. The role of CysLTs was evaluated in our experimental allergic rhinitis model in sensitized guinea pigs which shows biphasic nasal blockage, sneezing and nasal hyperresponsiveness to LTD4 induced by repetitive inhalation challenge with Japanese cedar pollen. In this model, the CysLT1 receptor antagonist pranlukast suppressed the late-phase nasal blockage but not early blockage and sneezing. Nasal hyperresponsiveness (nasal blockage) to LTD4 was largely blocked by pranlukast, naphazoline, and N omega-nitro-L-arginine-methyl ester. The results demonstrate that nasal blockage induced by CysLTs is mainly due to dilatation of nasal blood vessels, which can be induced by the nitric oxide produced through CysLT1 receptor activation. On the other hand, when pollen inhalation challenge was performed in the presence of nasal hyperresponsiveness, antigen-induced biphasic nasal blockage and sneezing were considerably enhanced and CysLTs contributed to both symptoms, suggesting that nasal hyperresponsiveness induces aggravation of antigen-induced nasal symptoms. The results presented in this study further suggest that our model is a good representative of human allergic rhinitis and offer evidence that CysLTs are chemical mediators mainly responsible for allergic nasal symptoms.

Topics: Allergens; Animals; Bronchial Provocation Tests; Chromones; Cryptomeria; Disease Models, Animal; Guinea Pigs; Humans; Inflammation Mediators; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lipoxygenase Inhibitors; Membrane Proteins; Pollen; Receptors, Leukotriene; Rhinitis, Allergic, Seasonal

To investigate the effect of omalizumab, a humanized monoclonal antibody, in addition to specific immunotherapy (SIT) on in vitro sulfidoleukotriene release (SLT) (A) before, (B) directly after, and (C) 1 yr after treatment with omalizumab. Children and adolescents (6.3-17.6 yr) with sensitization to birch and grass pollens and suffering from seasonal allergic rhinitis were included in a Phase III, placebo-controlled, multicenter clinical study. Within the four-arm study, patients were randomly chosen to receive SIT for either birch or grass pollen and either subcutaneous omalizumab or placebo for 24 wk during the pollen season. Thereafter, omalizumab or placebo treatment ended, but SIT therapy continued. Blood samples were collected from 92 (A, B) and 78 children (C), respectively. Leukocytes were isolated and stimulated with grass and birch pollen allergens. In the supernatants, SLT (LTC4, LTD4, LTE4) were measured using ELISA [cellular allergen stimulation test, DPC-Biermann, Germany]. At the end of treatment the combination of omalizumab + SIT-grass [median SLT-release: 2125 (before) and 416 ng/ml (after omalizumab treatment); p < 0.001] as well as omalizumab + SIT-birch [1404 and 207 ng/ml; p < 0.001] resulted in significantly lower SLT release after stimulation with the corresponding allergen compared to placebo + SIT-grass [2231 and 2490 ng/ml] or placebo + SIT-birch [1324 and 2489 ng/ml]. One year after omalizumab or placebo treatment, there was no significant difference in SLT release between the 4 groups (omalizumab + SIT-grass: 2855; SIT-grass + placebo: 2543; omalizumab + SIT-birch: 2417; SIT-birch + placebo: 2573 ng/ml). These results strongly suggest that the observed effects of decreased SLT release after omalizumab treatment were attributable to the treatment with omalizumab, rather than to SIT therapy.

Topics: Adolescent; Allergens; Anti-Allergic Agents; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Betula; Child; Combined Modality Therapy; Drug Monitoring; Female; Germany; Humans; Immunotherapy; Injections, Subcutaneous; Leukocytes; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Male; Omalizumab; Poaceae; Rhinitis, Allergic, Seasonal; Time Factors; Treatment Outcome

Recently, we were able to demonstrate that Omalizumab, a humanized monoclonal anti-IgE antibody, reduces in vitro leukotriene (LT) release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy. The aim of this study was to investigate the effect of anti-IgE in combination with specific immunotherapy (SIT) on urinary leukotriene E4 (LTE4) levels. Children and adolescents with sensitization to birch and grass pollens and suffering from seasonal allergic rhinitis were included in a phase III, placebo-controlled, multicenter clinical study. Within the four-arm study, patients were randomized to receive SIT for either birch or grass pollen and to receive either subcutaneous anti-IgE or placebo for 24 weeks during the pollen season. From a total population of 225 children, we collected three urine samples in a subgroup of 19 children [n = 12 boys (63%); mean age 11.8 years; range 7.2-17.5 years; Group A (n = 10): SIT (grass or birch) + anti-IgE; Group B (n = 9): SIT (grass or birch) + placebo]. Urine samples were collected before, during and at the end of treatment. Endogenous urinary LTE4 was separated by high-performance liquid chromatography (HPLC) and determined by enzyme immunoassay with a specific antibody. No differences in urinary LTE4 concentrations were observed between the anti-IgE and the placebo groups before (A: 35.2; B: 36.5 nmol/mol creatinine), during (A: 27.0; B: 29.3) and after treatment (A: 28.9; B: 26.5 nmol/mol creatinine). We conclude that urinary LTE4 levels are not helpful in monitoring patients treated with anti-IgE and SIT.

Topics: Adolescent; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibody Specificity; Biomarkers; Child; Child Welfare; Combined Modality Therapy; Desensitization, Immunologic; Female; Germany; Humans; Immunoglobulin E; Leukotriene E4; Male; Omalizumab; Rhinitis, Allergic, Seasonal; Treatment Outcome

Allergic rhinitis and bronchial asthma can coexist and affect each other.. To investigate the relationship between the postseasonal increase in the concentration of leukotriene (LT) B4 and LTE4 in exhaled breath condensate (EBC) and bronchial responsiveness to methacholine (BRM) in patients with seasonal allergic rhinitis (SAR).. In 28 patients with SAR and 50 healthy study patients, the leukotrienes were measured in EBC during and after the pollen season by gas chromatography/mass spectrometry. The BRM was determined after the pollen season.. In 7 patients with SAR, significantly increased concentrations of both the leukotrienes were found in EBC during and 5 months after the pollen season. The following seasonal and postseasonal median values were measured in patients with SAR in comparison with control patients: LTB4: 131 and 90 pg/mL vs 80 and 79 pg/mL, P < .001 and P = .03, respectively; LTE4: 122 and 86 pg/mL vs 76 and 74 pg/mL, P < .001 and P = .02, respectively. Five months after the pollen season, the concentrations of LTB4 and LTE4 decreased with respect to their seasonal values (90 and 86 pg/mL, respectively, P < .001, for both leukotrienes). In 7 patients with SAR and leukotriene levels exceeding the reference limits, significantly increased BRM was also found (LTB4: P = .02; LTE4: P = .002).. The seasonal and postseasonal increases in LTB4 and LTE4 concentrations in EBC of the patients with SAR correlated significantly with the later increase in BMR. This relationship could provide a useful predictive parameter for early inflammatory processes in the lower airways of patients with allergic rhinitis.

Topics: Adult; Anti-Asthmatic Agents; Asthma; Bronchi; Exhalation; Female; Humans; Leukotriene B4; Leukotriene E4; Male; Methacholine Chloride; Middle Aged; Reference Standards; Rhinitis, Allergic, Seasonal; Young Adult

Leukotrienes (LTs) are increased in exhaled breath condensate (EBC) in patients with asthma. So far no data have been reported about LT levels in nonasthmatic patients with seasonal allergic rhinitis (SAR). The aim of the study was to find out whether the LT levels in EBC were increased in the nonasthmatic adult patients with SAR both during and after the pollen season in comparison with healthy controls and to assess the changes of the LT levels after the pollen season.. Twenty-nine nonasthmatic adult patients with SAR underwent measurement of exhaled LTs in the EBC during and after the pollen season. Leukotrienes B(4), C(4), D(4) and E(4) were analysed by a specific and sensitive gas chromatography/mass spectrometry (GC/MS) assay and compared with 50 healthy nonsmoking controls. Spirometry, skin prick tests and nonspecific IgE were evaluated.. Leukotrienes concentrations (B(4), E(4) but not D(4)) were significantly increased in and after the pollen season in patients with SAR in comparison with healthy controls. In most of the samples, LT C(4) was undetectable. The values of all exhaled LTs were significantly decreased after the pollen season compared with the seasonal baseline: LTB(4) (P = 0.023), LTD(4) (P = 0.020), LTE(4) (P = 0.047).. Levels of exhaled LTB(4) and LTE(4) were higher in SAR patients than in healthy controls and decreased after the pollen season as compared with levels in season. The SAR patients with the highest in season LT levels had also the post-season levels elevated and this may be an early marker of inflammatory process in the lower airways despite the absence of clinical symptoms of asthma.

Topics: Adolescent; Adult; Case-Control Studies; Exhalation; Female; Humans; Leukotriene B4; Leukotriene E4; Male; Middle Aged; Osmolar Concentration; Pollen; Rhinitis, Allergic, Seasonal; Seasons

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

Lipid-derived mediators are found in nasal secretions during the early and late phase of allergic responses. To explore this early response further, concentrations of inflammatory mediators were measured along with characterization of specific cell influx during dose-dependent ragweed challenges. Ten allergic rhinitis subjects underwent two unilateral nasal lavages using 3-fold concentrations of short ragweed antigen. Low doses of ragweed (0.016-0.114 units Amb a I) did not provoke cell influx (1 of 18 challenges), whereas moderate doses (0.432-1.3 units Amb a I) induced cell influxes in 7 of 18 and at high doses in 8 of 17 challenges (3.39-11.7 units Amb a I). The differential of the cellular influx was greater than 50% neutrophils in 7 challenges; greater than 50% eosinophils in 3, and a mixed pattern in 6. There was a significant association between the dose of antigen and the level of prostaglandin D2 (PGD2), leukotrienes (LTs) C4, D4 and E4. Challenges with an eosinophilic influx tended to be associated with higher concentrations of mediators than neutrophilic influxes. Similar to the immediate skin response, the early allergic response in the nose demonstrated a cell influx with release of PGD2, LTsC4, D4 and E4. Nasal cellular inflammation therefore can occur within minutes of allergen exposure.

Topics: Allergens; Dose-Response Relationship, Immunologic; Eosinophils; Humans; Leukotriene E4; Leukotrienes; Nasal Mucosa; Neutrophils; Pollen; Prostaglandin D2; Rhinitis, Allergic, Seasonal; SRS-A

The leukotrienes LTC4, D4, and E4 are potent bronchoconstrictor agents and are thought to have an important role in asthma. Urinary LTE4, a stable urinary end-product of LTC4 and LTD4, was measured, by means of high-performance liquid chromatography and radioimmunoassay. LTE4 excretion followed a log-normal distribution in twenty-nine healthy controls, with a geometric mean of 23.8 (95% confidence interval 19.9-28.2) ng/mmol creatinine. Urine was collected from eight atopic subjects for 3 h after antigen inhalation and a control urine collection was made a week later at the same time of day. Urinary LTE4 was significantly higher after antigen challenge than in the control sample (153.7 [87.1-271.3] vs 23.5 [13.7-69.5] ng/mmol creatinine; p less than 0.01). Urinary LTE4 was also measured in twenty patients with severe acute asthma and nine patients with seasonal allergic rhinitis. 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. The urinary LTE4 values of the rhinitis patients were within the normal range whether or not they had symptoms. LTC4 and LTD4 were also found in bronchoalveolar lavage fluid from one of the three atopic subjects challenged with antigen before lavage, and in a single patient who underwent lavage after admission with severe acute asthma. These studies provide evidence that leukotrienes are released in vivo in man after antigen challenge and in acute asthma.

Topics: Acute Disease; Adult; Animals; Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Evaluation Studies as Topic; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Middle Aged; Mites; Peak Expiratory Flow Rate; Pollen; Rhinitis, Allergic, Seasonal; Skin Tests; SRS-A

Slow-reacting substance of anaphylaxis (composed of leukotrienes C, D, and E) is released in vitro by the interaction of antigen and IgE antibody on human mast cells and basophils. When we challenged ragweed-sensitive patients intranasally with pollen grains, their clinical response was significantly correlated with the release of the peptide leukotrienes (P less than 0.001). Nonallergic subjects had neither symptoms nor leukotriene release. The leukotrienes were released in a dose-dependent fashion, with a peak mean level of 827 +/- 234 pg per 0.1 ml of a 10-ml nasal wash. High-performance liquid chromatography revealed the presence of leukotrienes C, D, and E, suggesting that nasal cells or fluids had the ability to degrade leukotriene C enzymatically. The in vivo release of these potent inflammatory mediators after exposure to pollen suggests that leukotrienes may have an important role in human allergic reactions.

Topics: Adolescent; Adult; Allergens; Basophils; Chromatography, High Pressure Liquid; Female; Humans; In Vitro Techniques; Leukotriene E4; Male; Mast Cells; Middle Aged; Nasal Mucosa; Pollen; Rhinitis, Allergic, Seasonal; SRS-A