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

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(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.