Antigen-induced Late Asthmatic Response Research Articles

Effects of RS-601, a Novel Leukotriene D4/Thromboxane A2 Dual Receptor Antagonist, on Asthmatic Responses in Guinea Pigs

The effects of 4-[4-[5,5,6,6,6-pentafluoro-1-(4-fluorobenzene-sulfonamido)hexyl]phenyl]butyric acid (RS-601), a novel leukotriene D₄ (LTD₄)/thromboxane A₂ (TxA₂) dual receptor antagonist, on bronchial asthmatic responses in guinea pigs were examined. The effects were compared with those of pranlukast (LTD₄ receptor antagonist) and S-1452 (TxA₂ receptor antagonist). RS-601 inhibited the increase in airway resistance caused by LTD₄ and TxA₂ mimetic compound, U-46619, but not by histamine. RS-601 and pranlukast but not S-1452 inhibited an antigen-induced late asthmatic response. In addition, RS-601 inhibited an antigen-induced airway hyperresponsiveness (AHR), whereas pranlukast and S-1452 had no effect on the AHR. The antigen-induced increase in inflammatory cells in airway was not affected by all examined agents. Furthermore, bacterial lipopolysaccharide-induced AHR in guinea pigs was clearly suppressed by RS-601 but not by pranlukast and S-1452. The increase in airway inflammatory cells caused by lipopolysaccharide was not affected by all three drugs. These findings indicate that RS-601 has a potent antiasthmatic efficacy, especially on AHR, but does not affect accumulation of eosinophils in the airways.

Suppressive effects of F-1322 on the antigen-induced late asthmatic response and pulmonary eosinophilia in guinea pigs

We investigated the effects of F-1322 ( N-[2-[4-(benzhydryloxy)piperidino]ethyl]-3-hydroxy-5-(3-pyridylmethoxy)-2-naphthamide), a new compound that inhibits both thromboxane A 2 synthetase and 5-lipoxygenase and that functions as a histamine antagonist, on the Ascaris antigen-induced late asthmatic response and pulmonary eosinophilia in guinea pigs. Oral administration of F-1322 (10–100 mg/kg) inhibited the antigen-induced late asthmatic response in a dose-dependent manner. Histological analysis revealed that F-1322 prevented the accumulation of eosinophils in the airways and this was paralleled by a decrease in the number of eosinophils and lymphocytes recovered in bronchoalveolar lavage fluid. F-1322 (0.1–10 μM) inhibited eotaxin-induced chemotaxis and actin polymerization of eosinophils in vitro in a concentration-dependent manner, while oral administration of F-1322 dose-dependently suppressed the migration of eosinophils into the airways in vivo in response to infusion of interleukin 5 and eotaxin in combination. F-1322 may, thus, improve the late asthmatic response in this model, in part, by preventing the accumulation of eosinophils in the airways. The pharmacological profile of F-1322 indicates that this drug is likely to be useful in the treatment of allergic diseases such as asthma.

Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma

Background: APC 366, a selective inhibitor of mast cell tryptase, has been shown to inhibit antigen-induced early asthmatic response (EAR), late asthmatic response (LAR), and bronchial hyperresponsiveness (BHR) in a sheep model of allergic asthma. Objective: The purpose of this study was to investigate the effects of APC 366 on antigen-induced EAR, LAR, and BHR in mild atopic asthmatics not on any anti-inflammatory therapy. Methods: Sixteen mild atopic asthmatics, each with a demonstrable antigen-induced EAR, LAR, and BHR to histamine, were recruited into this randomized, double-blinded, crossover study. APC 366 (5 mg)/placebo was administered by aerosol inhalation 3 times per day on treatment days 1 through 4. Allergen challenge was carried out on day 4. Histamine challenge was performed the following morning, 1 hour after final dosing. Results: Subjects were shown to have a significantly smaller overall mean area under the curve for the LAR (P = .012) and mean maximum fall in FEV1 for the LAR (P = .007) after pretreatment with APC 366 in comparison with placebo. No significant effects on BHR were demonstrable. Although the EAR was reduced by 18% after treatment with APC 366 in comparison with placebo, this was not statistically significant. Conclusion: Short-term repeated administration of APC 366 significantly reduced the magnitude of antigen-induced LAR in atopic asthmatics, which supports the role of mast cell tryptase in the pathophysiology of the LAR. (J Allergy Clin Immunol 2001;107:1039-45.)

Effect of YM158, a Dual Lipid Mediator Antagonist, on Immediate and Late Asthmatic Responses, and on Airway Hyper-responsiveness in Guinea Pigs

The effects of lipid mediator antagonists: the LTD4-receptor antagonist pranlukast, the TXA2-receptor antagonist seratrodast, and the novel dual LTD4- and TXA2-receptor antagonist YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesulfonyl) propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) were investigated in animals exhibiting immediate asthmatic response (IAR), late asthmatic response (LAR) and airway hyper-responsiveness (AHR). Antigen-induced LAR and AHR are inhibited by orally administered pranlukast (30, 100 mg/kg) and seratrodast (3, 10 mg/kg). YM158 (30 mg/kg), orally administered before or after IAR induction, also inhibited both LAR and AHR. However, while the inhibitory effects of pranlukast and seratrodast on IAR were marginal, the effects of YM158 (3, 10, 30 mg/kg) were dose-dependent, probably due to its multiple sites of action. Additionally, orally administered YM158 (30 mg/kg) inhibited ozone-induced AHR in guinea pigs. Thus, an antagonist that inhibits several lipid mediators might exhibit greater efficacy in treating asthmatic responses than antagonists with a single site of action. Therefore, YM158 shows great promise as a drug that will be able to treat bronchial asthma and related disorders more potently than currently used single-pathway inhibitors.

Pharmacological Studies on the Novel Antiallergic Drug HQL-79: I. Antiallergic and Antiasthmatic Effects in Various Experimental Models

The effects of oral administration of 4-benzhydryloxy-1-{3-(1H-tetrazol-5-yl)-propyl}piperidine (HQL-79), a newly synthesized antiallergic drug, in various experimental allergic and asthmatic models were investigated. HQL-79 markedly inhibited immediate hypersensitivity reactions such as passive cutaneous anaphylaxis in rats, antigen-induced bronchoconstriction and nasal vascular permeability in actively sensitized guinea pigs, like epinastine and ketotifen did. Airway eosinophilia in repeatedly antigen-exposed guinea pigs was suppressed by chronic administration of HQL-79 for 2 weeks. In another experiment, the antigen-induced late asthmatic response (LAR) in metyrapone-treated guinea pigs was also ameliorated by chronic treatment with HQL-79. Moreover, HQL-79 partially inhibited the toluene diisocyanate-induced delayed-type hypersensitivity (DTH) reaction in mice when administered chronically during the immunization period. The corticosteroid dexamethasone inhibited the airway inflammatory responses in guinea pigs and the DTH in mice. These results indicate that HQL-79 has potent inhibitory effects on the immediate hypersensitivity reactions, and when administered chronically, it also inhibits airway eosinophilia, LAR and DTH, similarly to corticosteroids.

P-552 - Effect of F-1322 on antigen-induced late asthmatic response and spasmogen-induced bronchoconstriction.

P-552 - Effect of F-1322 on antigen-induced late asthmatic response and spasmogen-induced bronchoconstriction.

Antibody against interleukin-5 prevents antigen-induced eosinophil infiltration and bronchial hyperreactivity in the guinea pig airways

Interleukin-5 (IL-5) induces proliferation, differentiation and activation of eosinophils. An animal model of local allergen (airways) sensitization was employed to study the effects of anti-IL-5 monoclonal antibody (mAb) on infiltration of eosinophils into inflammatory region, the development of antigen-induced late asthmatic response (LAR) and the increased bronchial responsiveness following LAR. Guinea pigs exposed to aerosolized ovalbumin (OVA) daily for 10 days developed oped an increase in the number of eosinophils in the tracheal wall 24 h after aerosolized OVA challenge. Furthermore, all animals developed an apparent LAR determined by the response with a 2-fold increase in respiratory resistance and showed an increase in bronchial responsiveness to acetylcholine 24 h after OVA challenge. In animals treated with anti-IL-5 mAb, however, eosinophil number in the tracheal wall dramatically decreased compared with animals treated with control antibody. The development of LAR was also remarkably suppressed by anti-IL-5 mAb treatment, although a similar magnitude of immediate bronchoconstriction was observed. Moreover, in anti-IL-5 antibody-treated guinea pigs, an increase in bronchial responsiveness to acetylcholine significantly decreased. Data demonstrate that IL-5 is involved in airway eosinophilia, development of LAR and an increase in bronchial responsiveness induced by allergen sensitization via the airways. Development of IL-5 synthesis inhibitors and/or receptor antagonists could provide another therapeutic class of anti-asthmatic drugs.

Eosinophil Accumulation and Activation in Antigen-Induced Late Asthmatic Response in Guinea Pigs

The purpose of this study was to investigate the participation of airway eosinophils in the antigen-induced late asthmatic response (LAR) and increased airway responsiveness in the guinea pig model of asthma. After antigen challenge, guinea pigs sensitized with aerosolized ovalbumin showed a late-phase decrease in specific airway conductance, which was accompanied by airway hyperresponsiveness to histamine, eosinophilia in the bronchoalveolar lavage fluid (BALF), decreased BALF eosinophil density, and increased generation of superoxide anions from purified BALF eosinophils. We demonstrated an association of the LAR with eosinophil accumulation and activation in the airway.

Circadian Variation of Bronchial Caliber and Antigen-induced Late Asthmatic Response

To study whether circadian variation of bronchial caliber participates in causing late asthmatic response (LAR), house-dust inhalation was made at 10 AM and 6 PM on separate days in 6 house-dust-sensitive asthmatic children aged 8 to 13 years. Bronchial obstruction was assessed through measurements of FEV1 at 4-h intervals from 24 h before to 24 h after the inhalation. The LAR, which is a 15 percent or greater decrease in FEV1 from the value at the same hour of the previous day, occurred 4 h or later after the inhalation in all challenges. The mean (+/- SD) time to the occurrence of the lowest FEV1 (maximum LAR) following the morning inhalation was 14.7 +/- 2.1 h versus 10.0 +/- 2.2 h following the evening inhalation (p < 0.05). Regardless of the hour of inhalation, FEV1 after the inhalation was lowest or near-lowest at 2 AM in all. Therefore, the maximum LAR was indistinguishable from the trough of further amplified circadian variation in FEV1 following the inhalation. These findings suggest that the downward arm of circadian variation may partially participate in causing the LAR.

P-184 - Inhibition of antigen-induced late asthmatic response and airway inflammation by KW-4679.

P-184 - Inhibition of antigen-induced late asthmatic response and airway inflammation by KW-4679.

The effect of formoterol on the late asthmatic phenomena in guinea pigs

We investigated the effects of formoterol, a new, long-acting, selective β 2-adrenoceptor agonist, on the antigen-induced late asthmatic response (LAR) and airway inflammation in guinea pigs. Animals were sensitized by exposure to aerosolized ovalbumin (2% in saline). After antigen challenge, preceded by administration of an H 1-receptor antagonist, specific airway conductance was measured with a two-chambered whole-body plethysmograph. An aerosolized solution of formoterol, isoproterenol, or saline was inhaled 15 minutes before challenge. Bronchoalveolar lavage (BAL) was performed 24 hours after challenge. The provocative concentrations of histamine required to decrease specific airway conductance by 50% were obtained before challenge, at 24 hours, and at 72 hours after challenge. The LAR (52.7% ± 7.7% of the baseline; p < 0.02) was observed 6 to 8 hours after antigen challenge. An increased cellular influx in BAL (mainly eosinophils and macrophages) and an increased bronchial responsiveness to histamine occurred 24 hours after antigen challenge. Formoterol completely inhibited the LAR and the cellular increase in BAL; however, isoproterenol failed to prevent either the cellular infiltration or the LAR. Formoterol also decreased the antigen-induced increase in bronchial reactivity. These findings suggest that formoterol has inhibitory effects on the underlying inflammatory processes in antigen-induced asthma in addition to prolonged bronchodilation.

Inhibition of Antigen-Induced Late Asthmatic Response and Bronchial Hyperresponsiveness by Cyclosporin and FK 506

Using a guinea pig model of asthma, we have shown that the administration of cyclosporin, a T-lymphocyte-selective immunosuppressive agent, from the beginning of the immunization period inhibits the development of the late asthmatic response and bronchial hyperresponsiveness after antigen challenge. Similar results were obtained with FK 506, a new potent immunosuppressive agent. Since these compounds have been shown to suppress the activation of guinea pig T lymphocytes, the present data suggest that T lymphocytes may be important for the elicitation of the late asthmatic response and bronchial hyperresponsiveness.

Inhibition of antigen-induced late asthmatic response and bronchial hyperresponsiveness by cyclosporin A

We have previously demonstrated that Cyclosporin A (CyA), a T lymphocyte-selective immunosuppressive agent, reduced the delayed-phase bronchial eosinophil infiltration after antigen challenge in a guinea pig model of asthma. In the present study, we studied the effects of CyA on antigen-induced late asthmatic response (LAR) and bronchial hyperresponsiveness following LAR. Guinea pigs immunized by repeated exposure to aerosolized ovalbumin (OA) were intravenously given metopirone, a cortisol synthesis inhibitor, 24 hours before and 30 minutes before antigen challenge, and to prevent death from immediate severe bronchoconstriction, chlorpheniramine maleate was also injected. After antigen challenge with high dose of OA, LAR occurred in twelve of fifteen animals (80%) and the bronchial responsiveness to acetylcholine was significantly increased. However, when guinea pigs were treated with CyA from the beginning of immunization period, the development of LAR was completely inhibited, although similar magnitude of immediate bronchoconstriction was observed, and a subsequent increase in bronchial responsiveness was partially but significantly blocked. Since CyA has been shown to suppress activation of guinea pig T lymphocytes and their production of lymphokines, these results suggest that T cell factor(s) may be important for the elicitation of LAR and the antigen-induced bronchial hyperresponsiveness.

The requirement for polymorphonuclear leukocytes in the late asthmatic response and heightened airways reactivity in an animal model.

The antigen-induced late asthmatic response (LAR) and subsequent heightened airways reactivity after this response have been associated with increased airways inflammation. Employing an animal model of the LAR in rabbits previously developed in our laboratory, 3 phases of experiments were performed to investigate the role of polymorphonuclear leukocytes (PML) in the LAR and heightened reactivity. In all 3 phases, airways reactivity to histamine and bronchoalveolar lavage analysis were performed 3 days before and 3 days after bronchial challenge with ragweed extract. In Phase 1, 2 groups of rabbits receiving nitrogen mustard were studied: an immune group received immune serum containing antiragweed IgE, and a control group received nonimmune serum. In Phase II, nitrogen mustard was administered to immune rabbits during aortic occlusion to allow the lungs to be exposed to nitrogen mustard while limiting exposure of the bone marrow to this drug, preventing depletion of PML. In Phase III, both an immune and a nonimmune group of rabbits received nitrogen mustard as in Phase I; however, prior to antigen challenge, they were repleted with a neutrophil-rich population of PML. In all experiments, no group of control (nonimmune) rabbits, whether depleted or repleted of PML, developed an immediate asthmatic response (IAR) or a LAR. In addition, no significant increases in lavage cells or airways reactivity occurred after ragweed challenge. In contrast, those animals receiving immune serum and nitrogen mustard developed an IAR; however, no LAR occurred, and no significant change in airways reactivity was observed. Rabbits receiving immune serum and nitrogen mustard with aortic occlusion developed an IAR and LAR, and airways reactivity increased.(ABSTRACT TRUNCATED AT 250 WORDS)