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

(1)人类呼吸道轴突反射机制的证据在双盲、安慰剂对照的交叉试验中，10名哮喘患者在吸入缓激肽前20分钟给予速激肽受体拮抗剂(FK 224)或安慰剂，每隔5分钟给予一次。缓激肽在所有受试者中引起剂量依赖性的支气管收缩。FK 224明显反对支气管收缩效应；在服用安慰剂和服用FK 224后，导致比气道传导性下降35%所需累积浓度的几何平均值分别为5.3和40微克/毫升。吸入缓激肽导致三名受试者咳嗽，这三名受试者都被FK 224抑制。上述结果均被FK 224抑制。这些结果表明，哮喘患者的气道感觉神经释放速激肽参与了对缓激肽的反应。(Ii)神经源性炎症的调节。我们通过测量外渗量来观察NPY和异丁司特对豚鼠呼吸道神经源性微血管渗漏的影响。两个化合物均显著抑制刺激双侧迷走神经引起的反应，但外源性SP介导的反应不受这些药物的影响，提示这些药物可能通过预先抑制呼吸道感觉神经末梢释放神经肽来抑制神经源性渗漏。此外，我们还发现异丁司特的抑制作用是通过ATP敏感性钾通道实现的，而NPY的作用不是这样。(Iii)慢性呼吸道炎症模型我们检测了致敏豚鼠反复吸入变应原后兴奋性神经功能的变化。4周吸入变应原可显著增强胆碱能和非胆碱能支气管收缩，但不影响对外源性ACh和NKA的反应。我们认为这些神经功能的增强是通过增加神经递质的产生和/或释放所致。

(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.