Vagal bronchopulmonary C-fiber sensory nerves play an important role in regulating airway functions. Hypersensitivity of these afferents is believed to be involved in the manifestation of airway hyperresponsiveness associated with mucosal injury, a prominent feature of asthma. During airway inflammatory reaction, a number of low molecular weight, highly cationic proteins are secreted by inflammatory cells such as eosinophils that infiltrate into the airways. It is well documented that the release of these proteins can induce mucosal injury and airway hyperresponsiveness. Our recent studies have established the first direct evidence demonstrating an intense and sustained effect of both human eosinophil granule-derived and synthetic cationic proteins on vagal bronchopulmonary C-fiber endings. However, the mechanism underlying both the initial stimulatory and the sustained sensitizing effects of cationic proteins on these sensory nerves is poorly understood. Our central hypothesis is that the cationic charge carried by these proteins acts on the airway mucosa, triggering the release of certain inflammatory mediators that in turn exert potent effects on the C-fiber terminals. The mast cells located in the airway mucosa probably play an important role in the interaction between cationic proteins and sensory endings. Sensitization of these afferents can then lead to airway hyperresponsiveness via both cholinergic reflex pathways and tachykininergic mechanisms. Single-fiber and whole-cell patch-clamp recording techniques will be employed to measure the activity of bronchopulmonary C fibers in anesthetized rats and in isolated neurons, respectively. The results obtained from this study should provide critical information for gaining new insights into the mechanisms underlying the airway hyperresponsiveness induced by cationic proteins. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL058686-05A1
Application #
6967158
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Noel, Patricia
Project Start
1998-04-01
Project End
2009-06-30
Budget Start
2005-07-10
Budget End
2006-06-30
Support Year
5
Fiscal Year
2005
Total Cost
$256,025
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Lee, Lu-Yuan; Yu, Jerry (2014) Sensory nerves in lung and airways. Compr Physiol 4:287-324
Gu, Qihai; Lee, Lu-Yuan (2012) House dust mite potentiates capsaicin-evoked Ca2+ transients in mouse pulmonary sensory neurons via activation of protease-activated receptor-2. Exp Physiol 97:534-43
Gu, Qihai; Lee, Lu-Yuan (2011) Airway irritation and cough evoked by acid: from human to ion channel. Curr Opin Pharmacol 11:238-47
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; Lee, Lu-Yuan (2010) Acid-Sensing Ion Channels and Pain. Pharmaceuticals (Basel) 3:1411-1425
Hu, Youmin; Gu, Qihai; Lin, Ruei-Lung et al. (2010) Calcium transient evoked by TRPV1 activators is enhanced by tumor necrosis factor-{alpha} in rat pulmonary sensory neurons. Am J Physiol Lung Cell Mol Physiol 299:L483-92
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
Gu, Qihai; Lee, Lu-Yuan (2009) Effect of protease-activated receptor 2 activation on single TRPV1 channel activities in rat vagal pulmonary sensory neurons. Exp Physiol 94:928-36
Lee, Lu-Yuan (2009) Respiratory sensations evoked by activation of bronchopulmonary C-fibers. Respir Physiol Neurobiol 167:26-35

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