Bronchial hyperreactivity is a prominent feature of asthma. Indirect but compelling evidence suggests the possible involvement of increased pulmonary C-fiber excitability in the manifestation of bronchial hyperreactivity induced by airway mucosal injury. The objectives of this proposal are the following: 1) to characterize the stimulatory effect of hydrogen ions on pulmonary C-fibers, 2) to elucidate the mechanisms underlying this effect, and 3) to explore its potential role in the development of bronchial hyperreactivity. Proposed experiments are focused on two sources of H+ ions that are produced by tissue metabolism: lactic acid and CO2. An elevated level of lactic acid occurs commonly during severe exercise, tissue ischemia, and various pathologic conditions, but whether pulmonary C-fibers can be activated by excessive production of lactic acid is not known. The following three hypotheses will be tested: 1) pulmonary C-fibers can be activated by an increase in H+ concentration in pulmonary interstitial fluid (PIF), and lactic acid is particularly effective in stimulating these endings; 2) a substantial increase of CO2 tension in the alveolar gas can also exert a stimulatory effect on these afferents, and this action is brought about by an increase in the H+ concentration in the PIF; and 3) the stimulatory effect of H+ ions on these afferents can be potentiated by airway mucosal inflammation, in which the production and release of both cyclooxygenase metabolites and tachykinins are involved. In the proposed studies, mucosal inflammation will be induced by acute exposure of the lung to ozone or by hyperventilation with cold dry air. Pulmonary C-fiber afferent activity will be recorded in anesthetized rats by using a single-fiber recording technique, whereas pH in pulmonary venous blood will be measured continuously for estimation of the changes of pH in PIF during various experimental conditions. The relationship between changes in fiber activity and pulmonary venous pH will be established, and from this the threshold pH for stimulation can be determined. The feasibility and potential significance of the proposed studies have already been demonstrated in the preliminary experiments. These results will provide a more in-depth understanding of the chemosensitive properties of pulmonary C-fibers and their role in regulating the airway functions in various pathophysiological conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL058686-01A1
Application #
2631032
Study Section
Special Emphasis Panel (ZRG2-PHY (02))
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
832127323
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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