Pulmonary C-Neuron Hypersensitivity: Cellular Mechanisms

The long-range goal of this research project is to improve our understanding of the neural mechanisms involved in the development of bronchial hyperreactivity, which is a prominent pathophysiological feature of asthma. Increasing evidence indicates that hypersensitivity of vagal bronchopulmonary C-fiber sensory nerves plays a critical part in the manifestation of bronchial hyperreactivity associated with various airway inflammatory diseases. A recent study in our laboratory has reported the first evidence that the sensitivity of C-fiber endings in rat lungs is drastically elevated by increasing the intrathoracic temperature to a level comparable to the body temperature that occurs during strenuous exercise or severe fever (40.5-41 °C). Furthermore, it is well known that tissue inflammation can induce local hyperthermia. In fact, a higher tissue temperature has been recently reported in the airways of asthmatic patients. In light of the important role of pulmonary C fibers in regulating cardiopulmonary functions, the main objective of this proposal is therefore to investigate the mechanisms underlying the sensitizing effect of hyperthermia on these sensory nerves. Our hypothesis is that this effect is primarily mediated through the temperature-sensitive transient receptor potential vanilloid type (TRPV) ion channels that are expressed on C-fiber neurons. Activation of TRPVs causes membrane depolarization of these sensory nerves and lowers their thresholds to various physiological and pharmacological stimuli. Thus, hyperthermia-induced hypersensitivity of these afferents may lead to the development of airway hyperresponsiveness; this hypothesis is supported by our preliminary data. In addition, we hypothesize that chronic airway inflammation induced by allergen sensitization may up-regulate the sensitivity and/or expression of TRPV channels, and enhance the sensitizing effect of hyperthermia on pulmonary C fibers. Our preliminary studies have already demonstrated the feasibility and potential significance of the proposed studies. In summary, results obtained from this investigation are expected to bring new insights into the mechanisms underlying the hyperthermia-induced hypersensitivity of these sensory nerves in the airways, and the role of TRPV channels in regulating the sensitivity and function of these neurons.