Supplement: Role of TRPV1 in Asthma Exacerbation

Airway hypersensitivity, characterized by airway irritation, cough and bronchoconstriction, is a hallmark pathophysiological feature in airway inflammatory diseases such as asthma. The primary focus of this exploratory study is to investigate the role of transient receptor potential vanilloid type 1 receptor (TRPV1) in the pathogenesis of airway hypersensitivity. TRPV1, a ligand gated non-selective cation channel, exhibits distinct sensitivity to heat and is abundantly expressed in vagal bronchopulmonary C-fiber sensory nerves. Recent studies carried out in our lab have established the first evidence that the sensitivity of these pulmonary C-fiber neurons is markedly increased in response to an increase in temperature within the normal physiological range. More importantly, an increase in airway temperature by hyperventilating humidified hot air evoked bronchoconstriction and cough in patients with asthma, but not in healthy subjects. The airway constriction was mediated through vagal (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, our proposed study aims to test two 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 bronchoprovocation 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 inflammation. Thus, the 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 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 will provide new insights into the involvement of TRPV1 in the pathogenesis of airway hypersensitivity during asthma exacerbation, which should also help to uncover the mechanisms underlying the debilitating symptoms associated with airway inflammatory diseases.