Airway hypersensitivity, characterized by exaggerated sensory and reflexogenic responses to inhaled irritants, is a prominent pathophysiological feature of various airway inflammatory diseases (e.g., asthma, bronchitis, etc). Increasing and compelling evidence indicates that vagal bronchopulmonary C-fibers play a pivotal role in the manifestation of airway hypersensitivity. Recent investigations further suggest that the TRPV1 receptor, a non-selective cation channel and a polymodal transducer selectively expressed in C-fiber afferents, is likely involved in the airway hypersensitivity generated by airway inflammatory reaction. Indeed, a recent study in our lab has demonstrated that allergen sensitization-induced airway inflammation markedly enhanced the sensitivity of pulmonary C-fiber afferents and, more importantly, induced TRPV1 expression in myelinated pulmonary afferents that normally do not exhibit any capsaicin sensitivity. However, the physiological implication and the mechanism underlying the TRPV1 over- expression during airway inflammation are yet not fully understood. In this proposal, a research plan is designed to characterize the role of TRPV1 in the development of airway hypersensitivity when chronic airway inflammation is induced by allergen sensitization. Our hypothesis is that the enhanced airway sensitivity results from a combination of increased expression and excitability of this channel in the vagal bronchopulmonary sensory terminals. We further hypothesize that tumor necrosis factor 1, a pro-inflammatory cytokine and known to be released in the lung during allergic airway inflammation, is an important contributor to the over-expression of TRPV1 in these sensory neurons. Results obtained from these studies should provide important information about the mechanism that up-regulates the expression and excitability of the TRPV1 channel in the airway sensory neurons, and bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity caused by allergic airway inflammation. PUBLIC HEALTH RELEVANCE: In airway inflammatory diseases such as asthma and bronchitis, the respiratory tract becomes overly sensitive to inhaled irritants. This research proposal is designed to test our hypothesis that a specific ion channel, namely TRPV1, plays a major role in the exceedingly high excitability of airway sensory nerves caused by allergic inflammation. The results obtained from these studies should bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity.