Neurokinins Modulate Hyperventilation-induced Bronchoconstriction in Canine Peripheral Airways

Abstract

This study was designed to test the hypotheses that (1) neurokinin (NK) receptor activity modulates hyperventilation-induced bronchoconstriction (HIB) in canine peripheral airways and (2) NK receptor activity is stimulated via hyperventilation-induced eicosanoid production and release. A bronchoscope was used in anesthetized dogs to record peripheral airway resistance (Rp); to test airway reactivity to NK A (NKA), substance P, and hypertonic saline; and to examine HIB before and after combined treatment with NK-1 (CP 99,994) and NK-2 (SR 48,968) receptor antagonists. Bronchoalveolar lavage fluid cells, prostaglandin D2, and cysteinyl leukotrienes from hyperventilated airways pretreated with either vehicle or NK antagonists were also measured. Pretreatment with NK-1 and NK-2 antagonists significantly attenuated HIB and the response to substance P, virtually abolished the response to NKA, and had little effect on the response to HS. Blockade of NK-1 and NK-2 receptors did not affect either the cell profiles or the mediator concentrations recovered in bronchoalveolar lavage fluid after hyperventilation. We conclude that NKs modulate the development of HIB and appear to do so via hyperventilation-induced eicosanoid production and release.

Role of MUC5AC in the pathogenesis of exercise-induced bronchoconstriction

“…34 Similar results were identified in the dog model of hyperpnea-induced bronchoconstriction using a combination of NK1 and NK2 antagonists. 35 In the current study, we found that the release of cysLTs and NKA were strongly associated events, which suggests that the release of NKA may occur via the cysLT-associated activation of sensory nerves. These data are consistent with the findings in human subjects with asthma that a cysLTR 1 antagonist reduces the severity of NKA-induced and bradykinin-induced bronchoconstriction.…”

Epithelial regulation of eicosanoid production in asthma

“…In a guinea pig model of hyperpnea-induced bronchoconstriction (HIB), either a 5-LO inhibitor or a CysLT 1 antagonist inhibited HIB and the release of neurokinins, while a neurokinin 2 receptor antagonist inhibited HIB, but not the release of leukotrienes, suggesting that leukotrienes are involved in the release of neurokinins that cause bronchoconstriction (41). Similarly in a dog model, a combination neurokinin 1 and 2 receptor antagonist inhibited HIB and the generation of LTs that are known in this model to cause HIB (42). We demonstrated that mucin 5AC (MUC5AC), the predominant gel-forming mucin of goblet cells is released into the airways during EIB and is associated with the levels of CysLTs in the airways (43).…”

An update on the role of leukotrienes in asthma

“…Airway LTB 4 release has been identified following exercise challenge in some [54], but not all studies [53]. In animal models, the effects of LTs on hyperpnea-induced bronchoconstriction are mediated through tachykinins produced by sensory nerves [55,56]. Recent in vitro studies have demonstrated that LTs both increase excitability of sensory nerves and reduce excitation threshold for sensory nerves [57•].…”