s-145 and Bronchial-Hyperreactivity

Lung tissues produce a large amount of Thromboxane (Tx) A2. In addition to platelet aggregation and artery smooth muscle contraction, TxA2 strongly induces airway smooth muscle contraction and bronchial hyperresponsiveness. Not only TxA2, but many arachidonate cyclooxygenase metabolites such as PGD2, PGF2 alpha, PGH2, and others stimulate TP (PGH2/TxA2) receptor and can take a pathophysiological role for bronchial asthma. Several compounds competitively antagonizing TP receptor have been developed and being proved to have beneficial effects for treating of bronchial asthma in clinical. In this review the efficacy and usage of TP receptor antagonists for bronchial asthma was discussed.

Topics: Asthma; Benzoquinones; Bridged Bicyclo Compounds; Bronchi; Bronchial Hyperreactivity; Carbazoles; Fatty Acids, Monounsaturated; Heptanoic Acids; Humans; Prostaglandins; Receptors, Thromboxane; Sulfonamides; Thromboxane A2

It has been considered that thromboxane A2 (TXA2) is involved in the development of bronchial hyperresponsiveness (BHR), a characteristic feature of asthma. To ensure the involvement of TXA2 in BHR of asthma, effects of a 1-week treatment with two orally active TXA2 antagonists, BAY u 3405 and S-1452, on BHR were examined in 10 and 13 patients with stable asthma, respectively, in two consecutive double-blinded, randomized, placebo-controlled, two-phase crossover studies. Provocative concentration of methacholine causing a 20% fall in FEV1 (PC20-FEV1) with BAY u 3405 (0.78 (GSEM, 1.50) mg/ml) was significantly greater than the value with placebo (0.65 (GSEM, 1.46) mg/ml) (ratio 1.23 times, 95% CI 1.01 to 1.46: P = 0.0401). PC20-FEV1 was also significantly increased with S-1452 (0.43 (GSEM, 1.39) mg/ml) compared with placebo (0.29 (GSEM, 1.27) mg/ml) (ratio 1.75 times, 95% CI 1.05 to 2.45: P = 0.0189). Baseline pulmonary function was not altered by these treatments. These results may ensure that TXA2 is significantly involved in the BHR of asthma while the degree of contribution may be small.

Topics: Adolescent; Adult; Airway Resistance; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchoconstrictor Agents; Carbazoles; Cross-Over Studies; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Middle Aged; Prostaglandin Antagonists; Sulfonamides; Thromboxane A2

The aim of this study was elucidate the role of lipid mediators in bronchial hyperresponsiveness (BHR) and airway eosinophil accumulation 24 hours after an antigen challenge in guinea pigs. Thromboxane (TX) A2 receptor antagonist, S-1452 (1, 10 mg/kg), cysteinyl leukotriene (cLT) receptor antagonist, ICI-198, 615 (0.5, 5 mg/kg), platelet activating factor (PAF) receptor antagonist, E-6123 (1, 10 micrograms/kg), and each vehicle were intraperitoneally given 1 h before and 11 h after an ovalbumin (OVA) challenge. BHR to inhaled methacholine was measured and then bronchoalveolar lavage (BAL) was performed 24 h after the OVA challenge. The three drugs significantly inhibited BHR to methacholine, dose dependently. S-1452 significantly inhibited total cell counts (TCC). ICI-198, 615 significantly reduced both TCC and eosinophil percentage, but E-6123 did not alter TCC and cell differentiation in BAL fluid. Therefore, these results clearly showed that lipid mediators were involved in antigen-induced BHR and suggested that TXA2 and cLT may contribute to the penetration of inflammatory cells through capillary wall, still more cLT is concerned eosinophil accumulation with cell specificity. PAF dose not take part in the penetration of inflammatory cells.

Topics: Animals; Azepines; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Eosinophils; Fatty Acids, Monounsaturated; Guinea Pigs; Indazoles; Leukotriene Antagonists; Male; Membrane Proteins; Platelet Membrane Glycoproteins; Prostaglandin Antagonists; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Leukotriene; Receptors, Thromboxane; Triazoles

Thromboxane (Tx)A2 synthase inhibitors and thromboxane prostanoid (TP) receptor antagonists have been developed as anti-asthma drugs. TxA2 may contribute to airflow limitation and bronchial hyperresponsiveness, and these compounds have been demonstrated to improve them. However, it is not known whether TxA2 is involved in bronchial inflammation. To address this question, we explored the influences of OKY-046 (a TxA2 synthase inhibitor) and S-1452 (a TP receptor antagonist) on eosinophilic inflammation of the airways using a murine model. BALB/c mice sensitized with ovalbumin and challenged by repeated exposure to ovalbumin yielded marked eosinophilia in bronchoalveolar lavage fluid (BALF). Treatment with either compound significantly reduced the number of total cells and eosinophils in BALF in a dose-dependent manner. The production of interleukin (IL)-5, IL-2 and interferon (IFN)-gamma by antigen-stimulated splenic mononuclear cells (SMNC) was significantly decreased in mice treated with either compound compared to that in untreated mice. Furthermore, both compounds inhibited proliferation and cytokine production of SMNC in vitro. These results suggest that both OKY-046 and S-1452 are capable of inhibiting production of cytokines, which in turn inhibits eosinophil infiltration into the murine airway. Thus, both thromboxane A2 synthesis inhibitors and thromboxane prostanoid antagonists may be effective as anti-inflammatory drugs in the treatment of asthma.

Topics: Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cytokines; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Methacrylates; Mice; Mice, Inbred BALB C; Prostaglandin Antagonists; Pulmonary Eosinophilia; Thromboxane-A Synthase

1. Although repeated intranasal administration of interleukin-8 (IL-8) causes bronchial hyperresponsiveness (BHR) mediated via thromboxane A2 (TXA2) and airway neutrophil accumulation in guinea-pigs, the acute effect of inhaled IL-8 is unclear. We performed this study to clarify the acute effect of IL-8 on bronchial responsiveness and the role of TXA2. 2. The effects of inhaled IL-8 on bronchial responsiveness and of the TXA2 antagonists, S-1452 (0.01 and 0.1 mg kg-1) and ONO-NT-126 (1.0 or 10 micrograms kg-1), on IL-8-induced BHR were examined by use of a modified Konzett-Rössler method in guinea-pigs. 3. Inhaled IL-8 at 100 ng ml-1, which failed to induce significant changes in Pao (pressure at the airway opening), enhanced an increase in Pao induced by subsequent inhalations of ascending doses (50-200 micrograms ml-1) of methacholine and histamine, suggesting the potentiating effect of IL-8 on bronchial responsiveness. No significant leukocyte infiltration was observed histologically sixteen minutes after the IL-8 inhalation. Both S-1452 and ONO-NT-126 reduced the IL-8-induced BHR. 4. In conclusion, IL-8 rapidly causes BHR via TXA2 release in guinea-pigs.

Topics: Administration, Inhalation; Animals; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Fatty Acids, Monounsaturated; Guinea Pigs; Interleukin-8; Male; Prostaglandin Antagonists; Terfenadine; Thromboxane A2

To investigate the mechanisms of airway hyperresponsiveness (AHR), we examined the time course for asthmatic responses (including immediate asthmatic response (IAR), late asthmatic response (LAR), and AHR), airway inflammation (including edema in the airway, accumulation of inflammatory cells in bronchoalveolar lavage fluid (BALF), and mediator release including histamine and thromboxane A2 (TXA2) in BALF after the repeated provocation of aeroantigen in sensitized guinea pigs. Furthermore, we examined the effect of S-1452, a TXA2 receptor antagonist, on the antigen-induced airway obstruction and AHR in guinea pigs. We found that IAR occurred 1 min after every antigen inhalations. LAR was observed every 4 h after the inhalation of antigen without 1st or 2nd challenge. AHR was initially observed 4 h after the 5th inhalation of antigen, and then AHR was observed at every time measured even after the 6th provocation. The water content of the airway increased after the 2nd antigen inhalation. A number of leukocytes, especially eosinophils in BALF, was observed 30 min after the 2nd antigen inhalation. Desquamation of epithelia was observed 30 min after the 5th antigen inhalation. TXB2 and histamine in BALF were detected after the first antigen inhalation. These results suggest that LAR is caused by repeated airway inflammation such as eosinophilia and mediator release including TXA2. AHR may appear with the damages of lung tissue such as desquamation of epithelia. Oral administration of S-1452 (1 and 10 mg/kg) significantly inhibited LAR and AHR, assessed after the 6th antigen challenge. The present findings suggest that repeated antigen challenge causes airway inflammation and leads to the onset of LAR and AHR when became chronic. Furthermore, persistent generated TXA2 plays an important role in the pathogenesis of antigen-induced late-phase obstruction and AHR.

Topics: Airway Obstruction; Airway Resistance; Animals; Antigens; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchitis; Bronchoalveolar Lavage Fluid; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Male; Prostaglandin Antagonists; Pulmonary Edema; Thromboxane B2; Time Factors

Interleukin-8 (IL-8) has been shown to be a chemotactic factor for neutrophils, T-lymphocytes and eosinophils, but it is unknown whether the IL-8-induced inflammatory cell accumulation into the airways can cause the bronchial hyperresponsiveness (BHR) characteristic of asthma. IL-8 at a dose of 0.5 or 5 micrograms/kg was administered intranasally to guinea-pigs twice a week for 3 weeks. One day after the last administration, animals were anesthetized and artificially ventilated through tracheal cannula and lateral pressure at the cannula (Pao) was measured as an overall index of airway responses to increasing concentrations of inhaled histamine (25, 50, 100, and 200 micrograms/ml). The IL-8 treatment significantly enhanced bronchial responsiveness to histamine in a dose-dependent manner (ANOVA P < 0.01). The provocative concentration of histamine causing a 100% increase in Pao (PC100) at a dose of 0.5 and 5 micrograms/kg of IL-8 was 68.1 (GSEM 1.12) and 35.6 (GSEM 1.25) micrograms/ml, respectively. The latter was significantly (P < 0.01) lower than that in control animals treated with PBS (93.3 [GSEM, 1.14] micrograms/ml). The IL-8 treatment also induced a significant influx of neutrophils, but not eosinophils, in bronchoalveolar lavage (BAL) fluid (18.3 +/- 8.8 and 30.6 +/- 8.3% in animals treated with 0.5 and 5 micrograms/kg, respectively, of IL-8 vs 3.6 +/- 0.7% in phosphate buffered saline-(PBS)-treated animals). Furthermore, we examined the effect of the thromboxane receptor antagonist S-1452 (0.01 or 0.1 mg/kg, i.p. 24 and 1 h before anesthesia) on this IL-8 induced BHR. S-1452 significantly inhibited the BHR dose-dependently (ANOVA P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Intranasal; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Fatty Acids, Monounsaturated; Guinea Pigs; Interleukin-8; Male; Neutrophils; Receptors, Prostaglandin; Thromboxane A2

1. IgG1-mediated anaphylactic bronchoconstriction was elicited by intravenous administration of antigen to guinea-pig 2 days after passive sensitization with IgG1-rich serum, and this response was not affected by heating the serum (at 56 degrees C, for 4 h). IgE-mediated bronchoconstriction, provoked 14 days after passive sensitization with IgE-rich serum, was completely abolished by the heating of the serum. 2. S-1452 (10 mg kg-1, p.o.), a selective thromboxane (Tx) A2 antagonist, significantly but incompletely suppressed the IgG1-mediated bronchoconstriction, but did not affect the IgE-mediated one, while diphenhydramine (5 mg kg-1, i.v.), a histamine antagonist, almost completely inhibited both IgG1- and IgE-mediated bronchoconstriction. 3. Pretreatment with propranolol (1 mg kg-1, i.v.), a beta-adrenergic blocker, in addition to diphenhydramine, caused a long-lasting bronchoconstriction following antigen challenge in both animal models. This histamine-independent bronchoconstriction was markedly suppressed by S-1452 at a low dose of 0.1 mg kg-1. 4. A significant increase in bronchial responsiveness to i.v. acetylcholine (ACh), compared to the prechallenge value, occurred as early as 3 min and persisted for 24 h after antigen challenge in the IgG1 model, but was not observed in the IgE model. S-1452 (10 mg kg-1, p.o.) inhibited the IgG1-mediated bronchial hyperresponsiveness, as assessed 60 min after antigen challenge. 5. A marked elevation of TxB2 levels was observed in bronchoalveolar lavage fluid (BALF) 3 min after antigen challenge in the IgG1 model, while levels were not changed in the IgE model. In contrast, the plasma TxB2 level assessed 1 min after antigen challenge was increased in both the IgGI and IgE models.6. The results indicate that the inhibition of IgGl- but not IgE-mediated bronchoconstriction by higher doses of S-1452 may result from the suppression of increased bronchial responsiveness to allergic mediators such as histamine, which is probably due to TxA2 generated in the airway lumen rather than in plasma. In both the IgGI and IgE models, plasma TxA2 appeared to contribute directly to the bronchoconstriction, its action being almost completely masked by histamine-mediated bronchoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic beta-Antagonists; Animals; Antibodies, Monoclonal; Antigens; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchoconstriction; Diphenhydramine; Fatty Acids, Monounsaturated; Guinea Pigs; Immunoglobulin E; Immunoglobulin G; Male; Receptors, Prostaglandin; Thromboxane A2; Thromboxane B2

Long-lasting bronchial hyperresponsiveness to i.v. acetylcholine was observed in actively sensitized guinea-pigs after aerosol ovalbumin exposure. The response became significant at 7 h post-challenge and persisted for at least 120 h compared to the response of unsensitized animals. Pretreatment of animals with the specific thromboxane A2 receptor antagonist, S-1452 (calcium (1R,2S,3S,4S)-(5Z)-7-(((phenylsulfonyl)amino)bicyclo[2.2.1] hept-2-yl)hept-5-enoate dihydrate), almost completely inhibited the onset of bronchial hyperresponsiveness, as assessed at 24 and 120 h post-challenge. However, it was ineffective when administered at 1 h post-challenge or 2 h before assessment of bronchial responsiveness. Lung vascular injury occurred transiently immediately after antigen challenge, the kinetics of injury being associated with those for the production of thromboxane B2 in bronchoalveolar lavage fluid. The vascular injury was dramatically suppressed by pretreatment with S-1452. These findings suggest that acutely generated thromboxane A2 plays an important role in the pathogenesis of antigen-induced long-lasting bronchial hyperresponsiveness, probably by producing vascular damage in the lungs.

Topics: Acetylcholine; Administration, Inhalation; Aerosols; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endothelium, Vascular; Fatty Acids, Monounsaturated; Guinea Pigs; Immunization; Injections, Intravenous; Lung; Male; Ovalbumin; Prostaglandins; Pulmonary Artery; Receptors, Prostaglandin; Thromboxane A2

We examined both a possible association of bronchial hyperresponsiveness with lung inflammatory responses and the role of thromboxane (Tx) A2 in these responses after lipopolysaccharide (LPS) exposure in guinea pigs treated with metyrapone, a cortisol synthesis inhibitor. The increase in bronchial responsiveness to i.v. acetylcholine was transient, with a peak at 2 h after LPS exposure, which was associated with increases in TxB2 and tumor necrosis factor in bronchoalveolar lavage (BAL) fluid. However, the levels of 6-keto-prostaglandin (PG) F1 alpha, interleukin-1 and interleukin-6 in BAL fluid, and the influx of leukocytes in airway and pulmonary edema were not associated with bronchial hyperresponsiveness. Oral administration of S-1452, a selective TxA2 receptor antagonist, markedly suppressed bronchial hyperresponsiveness without affecting cellular responses, pulmonary edema and production of PGs and cytokines. These findings suggest that LPS-induced bronchial hyperresponsiveness is dependent on secondarily generated TxA2, which appears to be independent of lung inflammation.

Topics: Animals; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Cytokines; Fatty Acids, Monounsaturated; Guinea Pigs; Interleukin-1; Interleukin-6; Leukocytes; Lipopolysaccharides; Metyrapone; Pneumonia; Prostaglandins; Pulmonary Edema; Receptors, Prostaglandin; Thromboxane A2; Tumor Necrosis Factor-alpha

We evaluated the inhibitory effect of S-1452, a specific thromboxane (Tx) A2 receptor antagonist on the increase of airway responsiveness in 7 dogs after ozone exposure. Airway responsiveness to inhaled methacholine (Mch) was determined by Astograph (7 Hz oscillation technique), and at the same time TxB2, 6-keto-prostaglandin (PG) F1 alpha, PGE2 levels and total cell counts in the bronchoalveolar lavage fluid (BALF) were measured. Ozone exposure was carried out for 2 hr at an ozone level of 3.04 +/- 0.02 ppm (mean +/- SEM). Airway responsiveness to Mch increased significantly after ozone exposure (p less than 0.01), and this hyperresponsiveness was inhibited significantly by pretreatment with S-1452 (p less than 0.02). TxB2 and PGE2 levels in BALF did not change after ozone exposure, but the levels of 6-keto-PGF1 alpha decreased significantly after ozone exposure (p less than 0.05). Total cell counts in BALF increased significantly after ozone exposure (p less than 0.02). The decrease of 6-keto-PGF1 alpha levels and the increase of total cell counts were not affected by pretreatment with S-1452. These results suggest that S-1452 is protective against the increase of airway responsiveness induced by ozone exposure, and that TxA2 plays an important role in the hyperresponsiveness. But hyperresponsiveness may not be induced by hyperproduction of TxA2, but by the relative increase of TxA2 to PGI2.

Topics: Animals; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Dogs; Environmental Exposure; Fatty Acids, Monounsaturated; Female; Ozone; Receptors, Prostaglandin; Receptors, Thromboxane