Mechanisms of tachykinergic nerve-mediated severe bronchoconstriction and inflammation

Project Summary Substance P is a sensory nerve tachykinin neuropeptide capable of inducing bronchoconstriction and inflammation. We have recently shown that airway sensory nerve density and neuronal substance P expression are significantly increased in humans with eosinophilic asthma. We have also demonstrated that mice born to allergen-sensitized mothers or transgenic mothers with elevated interleukin-5 (a primary cytokine involved in eosinophil maturation and survival) recapitulate key features of human asthma including increased airway sensory nerve density and substance P expression. When these offspring are exposed to allergen, they develop lethal bronchoconstriction that is rescued by antagonists of substance P's target, neurokinin-1 receptors. The central hypothesis of this proposal is that increased airway substance P innervation causes lethal bronchoconstriction and potentiates eosinophilic inflammation after allergen challenge. In this proposal, we will determine the mechanism by which substance P mediates these effects using both cre-recombinase and pharmacologic methodology to 1) test the role of NK1 receptors on specific airway nerve subtypes (sensory and parasympathetic nerves) and smooth muscle 2) test the role of NK1 receptors and a novel substance P receptor, MrgprA1, on airway dendritic cells and 3) test the role of NK1 receptors on airway eosinophils both in isolation, and synergistically with CCR3 (the target of eotaxin, a potent eosinophil chemoattractant). Endpoints include measurement of airway responsiveness in vivo, eosinophil and dendritic cell activation using flow cytometry, and quantitative assessments of airway nerve density, substance P expression, and eosinophil and dendritic cell interactions with nerves using novel 3D confocal microscopy developed by our group. Results will identify novel pathways and drug targets in severe asthma.