Study of airway neurogenic inflammation in chronic animal model and the evidence of axon reflex mechanisms in human airways

慢性动物模型气道神经源性炎症研究及人类气道轴突反射机制的证据

基本信息

批准号：
04670455
负责人：
ICHINOSE Masakazu
金额：
$ 1.34万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至无数据
项目状态：
已结题

项目摘要

(1) Evidence of axon reflex mechanisms in human airwaysIn a double-blind, placebo-controlled, crossover trial, ten subjects with asthma were given a tachykinin receptor antaqonist (FK 224) or placebo by inhalation 20 min before challenge of bradykinin given with 5 min intervals. Bradykinin caused dose-dependent bronchoconstriction in all subjects. FK 224 significantly opposed the bronchoconstrictor effect ; the geometric mean of the cumulative concentration required to elicit a 35% fall in specific airway conductance was 5.3 mug/ml afater placebo and 40 mug/ml after FK 224. Inhalation of bradykinin caused coughing in three subjects, which was inhibited by FK 224 in all three. These results, which was inhibited by FK 224 in all three. These results suggest that tachykinin release from airway sensory nerves is involved in response to bradykinin in the patients with asthma.(II) Modulation of neurogenic inflammationWe examined the effect of NPY and ibudilast on neurogenic microvascular leakage in guinea-pig airways by measuring extravasation. Both compounds significantly inhibited bilateral vagal nerve stimulation-induced responses, but the exogenous SP-mediated responses were not influenced by these agents, suggesting that these drugs inhibit neurogenic leakage by prejunctional inhibition of neuropeptide release from airway sensory nerve terminals. Furthermore, we have shown that the inhibitory effect of ibudilast was via ATP-sensitive K channels but the effect of NPY was not.(III) Chronic airway inflammation modelWe examined the excitatory nerve function after repeated allergen inhalation challenge in sensitized guinea-pigs. 4 wks allergen inhalation significantly enhanced both cholinergic and noncholinergic bronchoconstriction without affecting the response to exogenous ACh and NKA.We concluded that the enhancement of these nerve function was caused by enhancing neurotransmitter production and/or release.

（1）人类气道中轴突反射机制的证据是双盲，安慰剂对照，跨界试验，十个患有哮喘的受试者被给予他的心动激素受体antaqonist（FK 224）或安慰剂或安慰剂或安慰剂，或者通过20分钟的攻击时间为5分钟间隔前Bradykinin挑战前20分钟。心动激肽在所有受试者中引起剂量依赖性的支气管收缩。 FK 224显着反对支气管收缩效应；引起特定气道电导率下降35％所需的累积浓度的几何平均值为5.3 mug/ml Afater安慰剂，FK 224后40毫克/ml。在三个受试者中吸入Bradykinin引起咳嗽，这三个受试者在所有三个受试者中都抑制了FK 224。这些结果在所有三个中都被FK 224抑制。这些结果表明，哮喘患者的速毒素从气道感觉神经中释放出对松曲素的反应。（ii）神经发生炎症的调节我们通过测量挤出量进行了豚鼠气道检查NPY和IBUDILAST对神经源性微血管泄漏的影响。两种化合物都显着抑制了双侧迷走神经刺激诱导的反应，但是外源SP介导的反应不受这些药物的影响，这表明这些药物通过促成神经肽从气道感觉神经终端释放神经肽释放而抑制神经源性泄漏。此外，我们已经表明，ibudilast的抑制作用是通过对ATP敏感的K通道进行的，但NPY的作用却没有。（iii）慢性气道炎症模型We检查了在敏化的豚鼠中反复的过敏原吸入挑战后检查了兴奋性神经功能。 4 WKS过敏原吸入显着增强了胆碱能和非胆碱能支气管收缩，而不会影响对外源性ACH和NKA的反应。我们得出的结论是，这些神经功能的增强是由增强神经递质产生和/或释放引起的。