Motoyasu Saito

Effect of a thromboxane A2 receptor antagonist (AA-2414) on bronchial hyperresponsiveness to methacholine in subjects with asthma

Bronchial hyperresponsiveness (BHR) to various stimuli is one of the major clinical features of bronchial asthma. In this study, the effect of a thromboxane A2 (TXA2) receptor antagonist, AA-2414, on BHR to methacholine was evaluated in 15 patients with asthma. The methacholine inhalation test was performed before and after oral administration of AA-2414 for 4 days (20 or 40 mg/day). The provocative concentration of methacholine producing a 20% fall in FEV1 (PC20) was measured as an index of BHR. There was a significant increase in PC20 (p less than 0.01) from 0.43 (geometric SEM, 1.42) mg/ml to 0.93 (geometric SEM, 1.43) mg/ml after 40 mg/day of AA-2414, whereas baseline values of FVC and FEV1 were not changed by the treatment. Twenty milligrams per day of AA-2414 did not alter the PC20 value nor the parameter of baseline pulmonary functions. These findings might support our hypothesis that the subthreshold concentration of TXA2 in the bronchial tissues, which has no effect on bronchomotor tone per se, may be involved in BHR in asthma. Further studies with more potent and specific TXA2 receptor antagonists are needed to confirm the conclusion.

Bronchial hyperresponsiveness and airway neutrophil accumulation induced by interleukin-8 and the effect of the thromboxane A2 antagonist S-1452 in guinea-pigs.

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 5μg/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 μg/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 5μg/kg of IL‐8 was 68.1 (Gsem 1.12) and 35.6 (Gsem 1.25) μg/ml, respectively. The latter was significantly (P < 0.01) lower than that in control animals treated with PBS (93.3 [Gsem, 1.14] μg/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 μg/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). PC100 was 94.0 (Gsem 1.19), 137.4 (Gsem 1.17) and 43.0 (Gsem 1.24) μg/ml with S‐1452 at doses of 0.01 and 0.1mg/ml and saline, respectively. We conclude that IL‐8 causes BHR and airway neutrophil inflammation, and that thromboxane A2 is important in the development of BHR induced by IL‐8.

Aerosolized acetaldehyde, but not ethanol, induces histamine–mediated bronchoconstriction in guinea–pigs

It was reported that ethanol–induced bronchoconstriction was associated with elevated serum levels of aectaldehyde and histamine in Japanese asthmatic patients, but there is no study to investigate the airway response to acetaldehyde. We performed this animal study to test the hypothesis that acctaldehyde has the bronchospastic action via histamine release. First, we investigated the airway response to ascending doses (31.3, 62.5, 125. and 250 MM) of inhaled ethanol or acctaldehyde in guinea–pigs. Secondly, guinea–pigs pretreated with intraperitoneal injection of saline or 20 mg/kg diphenhydramine inhaled acetaldehyde. Finally, guinea–pigs pretreated with intraperitoneal injection of saline or 0–5 mg/kg atropine sulfate inhaled acetaldehyde. Inhalation of acetaldehyde. but not ethanol, caused bronchoconstriction in a dose–dependent manner. The bronchoconstriction induced by inhaled acetaldehyde was completely prevented by pretreatment with diphenhydramine. Atropine had no preventing effect against the acetaldehyde–induced bronchoconstriction. In conclusion, acetaldehyde has the bronchospastic action via histamine release in guinea–pigs. It is suggested that histamine HI–antagonists may be available for preventing alochol–induced asthma.

INHIBITORY EFFECT OF INHALED PROCATEROL ON ANAPHYLACTIC BRONCHOCONSTRICTION AND THROMBOXANE A2 PRODUCTION IN GUINEA-PIGS

This study was designed to examine whether an inhaled β2‐agonist, procaterol, inhibits thromboxane A2 (TXA2) production induced by antigen challenge in passively sensitized guinea‐pigs in vivo. Antigen‐induced bronchoconstriction was markedly inhibited by pre‐treatment with procaterol. Inhaled procaterol significantly reduced in a dose‐dependent manner the increment in TXB2 concentration in bronchoalveolar lavage fluid obtained 5 min after antigen challenge. Aerosol administration of procaterol significantly inhibited bronchoconstriction induced by inhaled hislainine. These results suggest that inhalation of procalerol has an inhibitory effect on antigen‐induced TXA2 production as well as a protective effect against bronchoconstriction induced by bronchoactive agents.

Bronchoconstrictive Properties and Potentiating Effect on Bronchial Responsiveness of Inhaled Thromboxane A2 Analogue (STA2) in Guinea Pigs

Effect of subthreshold concentration of inhaled STA2, a thromboxane A2 (TXA2) analogue, on bronchial responsiveness to histamine was investigated in anesthetized and artificially ventilated guinea pigs. Percent increase in pressure of the airway opening (Pao) by aerosol histamine (50, 100 micrograms/ml) was significantly potentiated by subthreshold dose of aerosol STA2 (0.10 micrograms/ml) which was determined by dose-response curve of % increase in Pao by inhaled STA2 (0.033, 0.10, 0.33, 1.0 micrograms/ml). These results demonstrated that thromboxane A2 could contribute to bronchial hyperresponsiveness which is one of the major clinical features of bronchial asthma.

The effect of the neurokinin antagonist FK-224 on the cough response to inhaled capsaicin in a new model of guinea-pig eosinophilic bronchitis induced by intranasal polymyxin B

Eosinophilic bronchitis without asthma can cause a persistent non-productive cough which is resistant to bronchodilator therapy. To understand the mechanism of the cough in this disorder, an animal model of eosinophilic bronchitis was developed. Guinea-pigs were treated with transnasal administration of polymyxin B or saline twice a week for 3 weeks. The number of eosinophils in bronchoalveolar lavage fluid increased in polymyxin B-treated animals when compared with those treated with saline. In addition, histological examination showed that the number of eosinophils infiltrated into the tracheal epithelium increased; injury to the tracheal epithelium was greater in polymyxin B-treated animals. The numbers of coughs induced by saline and each concentration of capsaicin (10−18, 10−16, 10−14M) were greater in the polymyxin B-treated animals. FK-224 (a neurokinin receptor antagonist) decreased the heightened cough reflex in this animal model of eosinophilic bronchitis. These findings suggest that neuropeptides, and particularly neurokinins, are involved in the heightened cough receptor sensitivity in eosinophilic bronchitis without asthma. This has implications for better understanding of this disorder and its treatment.

Additive effect of continuous low-dose ofloxacin on erythromycin therapy for sinobronchial syndrome

It has been established that long-term low-dose erythromycin therapy (EM therapy) is very effective for sinobronchial syndrome, a common condition in Japan characterized by chronic upper and lower airway inflammation. The effect does not result from its bacteriocidal activity and the detailed mechanisms are not known. It takes 3-6 months for EM therapy to improve the symptoms. This study was designed to evaluate the additive effect of continuous low dosage or intermittent usual dosage of ofloxacin (OFLX) on EM therapy in patients with sinobronchial syndrome. Patients with sinobronchial syndrome were randomly allocated to receive one of the following four regimens. Patients in Group A received both low-dose OFLX and EM therapy daily for 6 months. Patients in Group B received EM therapy and intermittent treatment of OFLX for 6 months. Patients in Group C underwent EM therapy for 6 months. Patients in Group D received neither OFLX nor EM therapy. All patients were given carbocystein for more than 2 months before starting each treatment and during the study period. In patients receiving OFLX and/or EM therapy, these antimicrobial agents were well-tolerated during the treatment period. Amount of sputum in the morning was significantly less in Group C than in Group D after 3-6 months, and decreased significantly in Group A as compared with Group B after 2 weeks, Group C after 2 weeks to 2 months, and Group D after 2 weeks to 6 months. Other symptoms such as number of expectorations, difficulty of expectoration and severity of cough also improved rapidly in Group A. These findings suggest that it is useful to add low-dose OFLX to EM therapy for sinobronchial syndrome, especially within 1-2 months from starting treatment, and it may be cost-effective as this combination therapy can shorten the treatment period of EM therapy.

Involvement of arachidonate cyclooxygenase products in bronchial hyperresponsiveness induced by subthreshold concentration of aerosolized thromboxane A2 analogue (STA2) in guinea pigs.

Saito M, Fujimura M, Sakamoto S, Miyake Y, Shintani H, Yasui M, Matsuda T. Involvement of arachidonate cyclooxygenase products in bronchial hyperresponsiveness induced by subthreshold concentration of aerosolized thromboxane A2 analogue (STA2) in guinea pigs.

Role of thromboxane A2 and platelet-activating factor in allergic bronchoconstriction in guinea pig airway in vivo.

Membrane-derived lipid mediators have been considered to play a major role in pathogenesis of bronchial asthma. However, the importance of and the interactions among each mediator are still unclear. We examined the role of thromboxane A2 (TXA2) and platelet-activating factor (PAF) in immediate asthmatic response (IAR) and interactions between these lipid mediators in guinea pig airway in vivo using a specific TXA2 antagonist S-1452 and a specific PAF antagonist Y-24180. We confirmed the activity of each antagonist, as S-1452 and Y-24180 significantly and dose-dependently inhibited bronchoconstriction induced by respective agonist inhalation. S-1452 inhibited IAR but Y-24180 did not, indicating that TXA2 plays a major role in IAR but PAF does not. S-1452 significantly inhibited PAF-induced bronchoconstriction but Y-24180 did not inhibit synthesized TXA2 (STA2)-induced bronchoconstriction, showing that the bronchoconstrictive effect of PAF is at least in part dependent on secondarily released TXA2, but TXA2 does not induce PAF production.

Role of leukotrienes and platelet activating factor in allergic bronchoconstriction and their interactions in guinea pig airway in vivo.

Membrane-derived lipid mediators have been considered to play a major role in pathogenesis of bronchial asthma. Recently specific antagonists and synthetase inhibitors of some chemical mediators have been developed and many studies on their anti-asthmatic effects are ongoing. But the importance of and the interactions of each mediator are still unclear. We examined the role of leukotrienes (LTs) and platelet activating factor (PAF) in immediate asthmatic response (IAR) and interactions between these lipid mediators in guinea pig airways in vivo using a specific LTs antagonist AS-35 and a specific PAF antagonist Y-24180. We confirmed the activity of each antagonist, as AS-35 and Y-24180 inhibited bronchoconstriction induced by respective agonist inhalation. AS-35 inhibition IAR but Y-24180 did not, indicating that LTs play a major role in IAR but PAF does not. AS-35 did not influence PAF-induced bronchoconstriction and Y-24180 did not inhibit LTs-induced bronchoconstriction, showing that there is no interaction between LTs and PAF.