Role of TRPV1 in asthma exacerbation

University Of Kentucky, Lexington KY

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Abstract

? DESCRIPTION (provided by applicant): Inflammatory reaction is known to lead to an increase in tissue temperature, but whether airway tissue temperature increases during asthma exacerbation is not yet known. Transient receptor potential vanilloid type 1 receptor (TRPV1), a ligand gated non-selective cation channel with a distinct sensitivity to heat, is selectively and abundantly expressed in vagal bronchopulmonary C-fiber sensory nerves. A series of studies carried out in our lab have established the first evidence that an increase in temperature within the normal physiological range can activate and sensitize these TRPV1-expressing sensory neurons innervating the lung and airways; activation of these C-fiber afferents can elicit reflex bronchoconstriction, cough and other airway defense responses. Indeed, our recent study has demonstrated that an increase in airway temperature by hyperventilating humidified hot air triggered cough and bronchoconstriction in patients with mild and stable asthma, but not in healthy subjects. The airway constriction was mediated through cholinergic reflex because it was completely prevented by pretreatment with ipratropium. The accompanying airway irritation and coughing further suggested an involvement of airway sensory nerves, presumable TRPV1-expressing C-fiber afferents. In the light of these novel findings, this proposed study aims to tes the following hypotheses: 1) in patients with allergic asthma, the airway tissue temperature is elevated locally in the region when the inflammatory reaction is evoked by a segmental bronco-provocation with allergen. 2) Both the thermal sensitivity of these neurons and the expression of TRPV1 at the sensory nerve terminals are enhanced by chronic airway allergic inflammation. Thus, a slight increase in local tissue temperature can lower the activation thresholds and enhance the sensitivity of TRPV1-expressing C-fiber sensory nerves in the airways of asthmatics. The synergistic effects of these factors may play a major part in the development of the airway hypersensitivity during chronic inflammation. This translational study will be performed in both asthmatic patients and in an animal model of allergic asthma. Results obtained from these studies should provide novel insights into the involvement of TRPV1 in the pathogenic mechanisms of airway hypersensitivity, and help to uncover the mechanisms underlying the debilitating symptoms associated with airway inflammatory diseases.