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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL067379-01A1
Application #
6469494
Study Section
Respiratory Physiology Study Section (RESP)
Program Officer
Noel, Patricia
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
1
Fiscal Year
2002
Total Cost
$253,400
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Lin, Yu-Jung; Lin, Ruei-Lung; Ruan, Ting et al. (2015) A synergistic effect of simultaneous TRPA1 and TRPV1 activations on vagal pulmonary C-fiber afferents. J Appl Physiol (1985) 118:273-81
Khosravi, Mehdi; Collins, Paul B; Lin, Ruei-Lung et al. (2014) Breathing hot humid air induces airway irritation and cough in patients with allergic rhinitis. Respir Physiol Neurobiol 198:13-9
Lee, Lu-Yuan; Gu, Qihai; Xu, Fadi et al. (2013) Acid-sensing by airway afferent nerves. Pulm Pharmacol Ther 26:491-7
Kou, Yu Ru; Kwong, Kevin; Lee, Lu-Yuan (2011) Airway inflammation and hypersensitivity induced by chronic smoking. Respir Physiol Neurobiol 178:395-405
Lee, Lu-Yuan; Gu, Qihai; Lin, You-Shuei (2010) Effect of smoking on cough reflex sensitivity: basic and preclinical studies. Lung 188 Suppl 1:S23-7
Gu, Qihai; Lim, Michelle E; Gleich, Gerald J et al. (2009) Mechanisms of eosinophil major basic protein-induced hyperexcitability of vagal pulmonary chemosensitive neurons. Am J Physiol Lung Cell Mol Physiol 296:L453-61
Lee, L-Y; Gu, Q (2009) Cough sensors. IV. Nicotinic membrane receptors on cough sensors. Handb Exp Pharmacol :77-98
Lee, Lu-Yuan (2009) Respiratory sensations evoked by activation of bronchopulmonary C-fibers. Respir Physiol Neurobiol 167:26-35
Lin, Ruei-Lung; Hayes Jr, Don; Lee, Lu-Yuan (2009) Bronchoconstriction induced by hyperventilation with humidified hot air: role of TRPV1-expressing airway afferents. J Appl Physiol (1985) 106:1917-24
Gu, Qihai; Lin, You-Shuei; Lee, Lu-Yuan (2007) Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of beta3-adrenoceptor. J Appl Physiol 102:1545-55

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