Pulmonary C-Neuron Hypersensitivity: Cellular Mechanisms

Grants and Contracts Details

Description

The long-range goal of this research project is to understand the neurogenic mechanisms underlying the bronchial hyperreactivity caused by inflammation of airway mucosa. Increasing evidence suggests an involvement of hypersensitivity of bronchopulmonary C-fiber afferents in the manifestation of bronchial hyper-reactivity induced by airway epithelial injury. The primary objective of this proposal is to investigate the role of endogenous prostaglandin E2 (PGE2), a potent autacoid, in the sensitization of bronchopulmonary C fibers caused by airway mucosal inflammation, and to elucidate the cellular mechanisms involved in this action. PGE2 is locally synthesized and releases from airway epithelium during various inflammatory reactions, and our recent studies have demonstrated a sensitizing effect of exogenous PGE2 on the pulmonary C fibers. The central hypothesis of this study is that endogenous PGE2 increases the sensitivity of the pulmonary C-fiber endings by activating EP2 and/or EP4 prostanoid receptors; activation of these EP receptors enhances the neuronal excitability by activating the cyclic AMP/protein kinase A signaling pathway that leads to modulation of the function of tetrodotoxin-resistant sodium channel. Proposed experiments will be carried out to test these hypotheses in rats using both in vivo (single-fiber recording) and in vitro (whole-cell patch-clamp recording) preparations; the latter will be performed in isolated nodose and jugular ganglion neurons innervating the lung and airways. The results obtained from this study should provide crucial information for gaining new insight into the signaling transduction mechanisms underlying the PGE2-induced sensitization of pulmonary C neurons. This information may, therefore, help to develop new therapeutic strategies for alleviating the symptoms of bronchial hyperreactivity associated with airway mucosal inflammation.
StatusFinished
Effective start/end date4/1/028/16/07

Funding

  • National Heart Lung and Blood Institute: $1,086,000.00

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