Grant: Project Grant

The airways of asthma patients are sensitive to inhaled allergens, like pollen. Long term allergen exposure increases lung inflammation and sensitization; once sensitized, exposure can trigger acute asthmatic attacks involving intense anxiety, airway narrowing, impaired breathing and, in severe cases, death. In recent rodents studies, we showed that during an allergen-induced asthmatic attack, the asthmatic lung releases chemicals into the general circulation that trigger a powerful neuronal reflex pathway causing airway narrowing. This pathway involves activation of the carotid bodies (nerve clusters in the neck) via specific receptors called TRPV1. Importantly, pharmacological disruption of this pathway with a single drug dose dramatically reduces airway narrowing and the breathing pattern associated with respiratory distress. These effects were long lived (days). Moreover, our preliminary data suggest that when carotid bodies are removed entirely, the lung inflammation and sensitivity to allergens associated with asthma is reduced. These observations lead to three important questions: 1/ How do chemicals from the lung activate the nerves associated with the carotid body; 2/ Does blocking the mechanisms involved have long-term beneficial effects on asthmatic lung health; 3/ Can blocking this reflex pathway reduce asthmatic symptoms in humans? This proposal addresses these questions with the aim of identifying novel targets to improve asthma treatment and prevent asthma-related morbidity and death. Specifically, we will determine how chemicals from the lung activate the carotid body using state-of-the-art experimental preparations and functional cellular imaging techniques, and test the consequences of blocking this signaling using surgical isolation, pharmacological and modern gene manipulation techniques. Finally, we will test whether blocking carotid body signalling using a best-in-class drug developed in Canada can reduce symptoms in human asthma sufferers.