thromboxane-a2 and Rhinitis--Allergic--Seasonal

Allergen-specific immunotherapy (IT) is widely used to treat allergic diseases. The molecular mechanisms have not been clarified yet completely. The present work was undertaken to analyze the effect of IT in the activation of NF-κB.. Neutrophils from 15 pollen-allergic IT-treated patients, 10 untreated pollen-allergic patients, and 10 healthy donors were in vitro stimulated with LPS. NF-κB activation (p65/p52) was measured in their nuclear extracts by enzyme-linked immunosorbent assay (ELISA). IκBα phosphorylation, NF-κB-repressing factor (NRF) activation, and thromboxane A2 (TXA2 ) and Interleukin-8 (IL-8) release were measured by ELISA.. There was a positive correlation between the score of symptoms and NF-κB activation in human neutrophils. IT significantly decreased NF-κB activation levels in neutrophils compared with neutrophils from untreated patients. IκBα phosphorylation and NRF activation levels were, respectively, significantly lower and higher in neutrophils from IT-treated patients than from untreated patients. IL-8 and TXA2 release were significantly lower in neutrophils from IT-treated patients than from untreated patients.. IT positive effects are at least in part mediated by the negative regulation of NF-κB activation in human neutrophils. These observations represent a novel view of neutrophils as possible cell target to treat IgE-dependent diseases through NF-κB downmodulation.

Topics: Adolescent; Allergens; Case-Control Studies; Cells, Cultured; Dactylis; Desensitization, Immunologic; Down-Regulation; Female; Humans; I-kappa B Proteins; Inflammation Mediators; Interleukin-8; Lipopolysaccharides; Male; Neutrophils; NF-kappa B; NF-kappa B p52 Subunit; NF-KappaB Inhibitor alpha; Phosphorylation; Pollen; Repressor Proteins; Rhinitis, Allergic, Seasonal; Signal Transduction; Thromboxane A2; Transcription Factor RelA; Treatment Outcome

Although thromboxane (TX)A2 is involved in allergic rhinitis, the mechanisms inducing nasal blockage have not been elucidated. We evaluated the roles of nasal mucosal vascular changes following intranasal instillation of the TXA2 analog U-46619 or leukotriene (LT)D4 to induce nasal blockage in a guinea pig model of allergic rhinitis. Both U-46619- and LTD4-induced nasal blockages in sensitized animals were swiftly and completely suppressed by a vasoconstrictor, naphazoline. The nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester relieved LTD4-induced nasal blockage, but not U-46619-induced nasal blockage. Although both agonists produced vasodilatation of nasal mucosa in vivo, LTD4 caused vasodilatation while U-46619 caused vasoconstriction in vitro. Both LTD4- and U-46619-induced nasal blockages in vivo should depend on vasodilatation of nasal mucosa. LTD4-induced nasal blockage is induced by direct vasodilatation via nitric oxide. In contrast, U-46619-induced nasal blockage may be associated with contraction of a certain vein that should exist at the exit of capacitance vessels, leading to congestion of the nasal mucosa.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Blood Vessels; Disease Models, Animal; Drug Synergism; Guinea Pigs; Leukotriene D4; Male; Models, Biological; Naphazoline; Nasal Mucosa; Nasal Obstruction; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phenylephrine; Pollen; Rhinitis, Allergic, Seasonal; Thromboxane A2

The purpose of this study was to investigate the involvement of chemical mediators other than histamine in nasal allergic signs using histamine H(1) receptor-deficient mice. In passively sensitized mice, antigen instillation into the nasal cavity induced significant increases in sneezing and nasal rubbing in wild-type mice, but no such increases were observed in histamine H(1) receptor-deficient mice. In actively sensitized mice, both sneezing and nasal rubbing were also significantly increased in a dose-dependent manner in both wild-type and histamine H(1) receptor-deficient mice. Histamine H(1) receptor antagonists such as cetirizine and epinastine significantly inhibited antigen-induced nasal allergic signs in wild-type mice, although the effects were incomplete. In addition, the thromboxane A(2) receptor antagonist ramatroban also inhibited these responses in wild-type mice. However, the leukotriene receptor antagonist zafirlukast showed no effects in wild-type mice. These results suggested that in the acute allergic model (passive sensitization), only histamine H(1) receptors are related to nasal signs induced by antigen, whereas in the chronic allergic model (active sensitization), both histamine H(1) receptors and thromboxane A(2) receptors were involved in the responses.

Topics: Animals; Anti-Allergic Agents; Antigens; Behavior, Animal; Carbazoles; Cetirizine; Dose-Response Relationship, Drug; Female; Histamine H1 Antagonists; Immunization; Immunoglobulin E; Indicators and Reagents; Indoles; Leukotriene Antagonists; Mice; Mice, Knockout; Ovalbumin; Passive Cutaneous Anaphylaxis; Phenylcarbamates; Receptors, Histamine H1; Rhinitis, Allergic, Seasonal; Sneezing; Sulfonamides; Thromboxane A2; Tosyl Compounds

We investigated the effects of the thromboxane (TX) A2 antagonist seratrodast, the peptide leukotriene (p-LT) antagonist pranlukast, the antihistaminic drug terfenadine and the glucocorticoid dexamethasone on antigen-induced sneezing, biphasic nasal blockage and nasal hyperresponsiveness to histamine using a guinea pig model of allergic rhinitis.. Male Hartley guinea pigs were used.. Intranasally sensitized guinea pigs were challenged once every week for 13 weeks by inhalation of Japanese cedar pollen as the antigen. Dexamethasone and other agents were administered orally 3 and 1 h, respectively, before the 4th, 6th and 13th challenge.. Sneezing frequency and the change in specific airway resistance (sRaw) were measured at these challenges. Two days after the 13th challenge, nasal responsiveness to histamine was evaluated by measuring sRaw after intranasal instillation of increasing doses of histamine. Moreover, the levels of TXB2, p-LTs and histamine were estimated in nasal cavity lavage fluid (NCLF) collected at the 13th challenge.. Only terfenadine (10 mg/kg) significantly inhibited sneezing at any challenge time. Seratrodast (3 and 10 mg/ kg), pranlukast (30 mg/kg) and dexamethasone (10 mg/kg), but not terfenadine, suppressed both the early and late phase elevation of sRaw (biphasic nasal blockage), although the degree of inhibition on the early phase response varied with the challenge time. In contrast, the development of nasal hyperresponsiveness to histamine was inhibited by only dexamethasone. Furthermore, biphasic increases in TXB2, p-LTs and histamine in NCLF were observed after the challenge in sensitized animals.. These results suggest that TXA2 and p-LTs, but not histamine, play important roles in both the early and the late phase nasal blockage in this model of allergic rhinitis.

Topics: Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Benzoquinones; Chromones; Dexamethasone; Guinea Pigs; Heptanoic Acids; Histamine; Histamine Release; Leukotrienes; Male; Nasal Cavity; Nasal Obstruction; Rhinitis, Allergic, Seasonal; Sneezing; Terfenadine; Therapeutic Irrigation; Thromboxane A2

We characterized the leukocyte kinetics after antigen challenge, and investigated the effects of the thromboxane (TX) A2 antagonist seratrodast, the peptide leukotriene (p-LT) antagonist pranlukast, the antihistaminic drug terfenadine and the glucocorticoid dexamethasone on this leukocyte response in a guinea pig model of allergic rhinitis.. Male Hartley guinea pigs were used.. Intranasally sensitized guinea pigs were challenged once every week for 15 weeks by inhalation of Japanese cedar pollen as the antigen. Dexamethasone and other agents were administered orally 3 and 1 h, respectively, before the 15th challenge.. The time-related changes in the numbers of differential leukocytes in nasal cavity lavage fluid (NCLF) and in peripheral blood after pollen inhalation challenge were investigated. The effects of the drugs on the antigen-induced changes in the leukocyte counts were evaluated. In addition, histopathological examination of the nasal mucosa was also performed 5 h after the challenge.. There was a marked increase in the number of leukocytes in NCLF, especially of eosinophils, which peaked at 5 h, after antigen challenge in this model. This response was also accompanied by the peripheral blood eosinophilia and neutrophilia. Seratrodast (30 mg/kg), pranlukast (30 mg/kg) and dexamethasone (10 mg/kg) inhibited the eosinophilia in all of the blood, the nasal mucosa and NCLF seen 5 h after the antigen challenge. Terfenadine (10 mg/kg) had no apparent effect on the blood and the mucosal eosinophilia, although it tended to suppress the eosinophil accumulation in NCLF.. These results suggest that the present model is useful for analyzing the mechanisms of antigen-induced eosinophilic inflammation in allergic rhinitis and that both TXA2 and p-LTs, but not histamine, contribute to the antigen-induced eosinophilia in this model of allergic rhinitis.

Topics: Administration, Intranasal; Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Antigens; Benzoquinones; Chromones; Dexamethasone; Guinea Pigs; Heptanoic Acids; Kinetics; Leukocyte Count; Leukocytes; Leukotriene Antagonists; Male; Nasal Cavity; Rhinitis, Allergic, Seasonal; Terfenadine; Therapeutic Irrigation; Thromboxane A2

To identify the chemical mediators involved in the pathogenesis of allergic rhinitis, we studied the effects of the thromboxane (TX) A2 receptor antagonist seratrodast, the peptide leukotriene receptor antagonist pranlukast and the antihistamine azelastine using a guinea pig model of allergic rhinitis. In guinea pigs actively sensitized by aerosol inhalation of antigen, antigen challenge into the nasal cavity increased both the nasal vascular permeability and the intranasal pressure; it also induced swelling of the nasal mucosa, which was evaluated by magnetic resonance imaging. Both seratrodast and azelastine significantly inhibited these antigen-induced responses when the drugs were administered p.o. 1 hr before antigen challenge. Also, the TX synthetase inhibitor ozagrel reduced the antigen-induced increase in nasal vascular permeability. On the other hand, pranlukast had little effect on the antigen-induced increases in nasal vascular permeability and intranasal pressure. Perfusions and inhalations of U-46619, a stable TXA2 mimetic, or of histamine into the nasal cavity caused concentration-dependent increases in nasal vascular permeability and intranasal pressure in normal guinea pigs. Leukotriene C4 also induced these responses, but the maximal responses to leukotriene C4 were less than the maximal responses to U-46619 or histamine. On the other hand, these responses were not induced by prostaglandin D2 or prostaglandin F2alpha. Moreover, the U-46619- and histamine-induced increases in vascular permeability and intranasal pressure were significantly inhibited by seratrodast and azelastine, respectively. In addition, levels of TXB2, a stable breakdown product of TXA2, and histamine in nasal lavage fluid increased after antigen challenge in actively sensitized guinea pigs. These results suggest that TXA2 and histamine play important roles in the pathogenesis of experimental allergic rhinitis in guinea pigs.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antigens; Benzoquinones; Capillary Permeability; Guinea Pigs; Heptanoic Acids; Histamine; Histamine H1 Antagonists; Male; Nasal Mucosa; Phthalazines; Prostaglandin Antagonists; Prostaglandin Endoperoxides, Synthetic; Rhinitis, Allergic, Seasonal; Thromboxane A2