Airway hypersensitivity, characterized by exaggerated sensory and reflexogenic responses to inhaled irritants, is a prominent pathophysiological feature of various airway inflammatory diseases (e.g., asthma, bronchitis, etc). Increasing and compelling evidence indicates that vagal bronchopulmonary C-fibers play a pivotal role in the manifestation of airway hypersensitivity. Recent investigations further suggest that the TRPV1 receptor, a non-selective cation channel and a polymodal transducer selectively expressed in C-fiber afferents, is likely involved in the airway hypersensitivity generated by airway inflammatory reaction. Indeed, a recent study in our lab has demonstrated that allergen sensitization-induced airway inflammation markedly enhanced the sensitivity of pulmonary C-fiber afferents and, more importantly, induced TRPV1 expression in myelinated pulmonary afferents that normally do not exhibit any capsaicin sensitivity. However, the physiological implication and the mechanism underlying the TRPV1 over- expression during airway inflammation are yet not fully understood. In this proposal, a research plan is designed to characterize the role of TRPV1 in the development of airway hypersensitivity when chronic airway inflammation is induced by allergen sensitization. Our hypothesis is that the enhanced airway sensitivity results from a combination of increased expression and excitability of this channel in the vagal bronchopulmonary sensory terminals. We further hypothesize that tumor necrosis factor 1, a pro-inflammatory cytokine and known to be released in the lung during allergic airway inflammation, is an important contributor to the over-expression of TRPV1 in these sensory neurons. Results obtained from these studies should provide important information about the mechanism that up-regulates the expression and excitability of the TRPV1 channel in the airway sensory neurons, and bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity caused by allergic airway inflammation.

Public Health Relevance

In airway inflammatory diseases such as asthma and bronchitis, the respiratory tract becomes overly sensitive to inhaled irritants. This research proposal is designed to test our hypothesis that a specific ion channel, namely TRPV1, plays a major role in the exceedingly high excitability of airway sensory nerves caused by allergic inflammation. The results obtained from these studies should bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096914-02
Application #
7924813
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Noel, Patricia
Project Start
2009-09-01
Project End
2012-12-31
Budget Start
2010-09-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2010
Total Cost
$356,462
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Lin, Ruei-Lung; Gu, Qihai; Khosravi, Mehdi et al. (2017) Sustained sensitizing effects of tumor necrosis factor alpha on sensory nerves in lung and airways. Pulm Pharmacol Ther 47:29-37
Zhao, Lei; Zhuang, Jianguo; Gao, Xiuping et al. (2016) From the Cover: Prenatal Nicotinic Exposure Attenuates Respiratory Chemoreflexes Associated With Downregulation of Tyrosine Hydroxylase and Neurokinin 1 Receptor in Rat Pup Carotid Body. Toxicol Sci 153:103-11
Zhao, Lei; Zhuang, Jianguo; Zang, Na et al. (2016) Prenatal nicotinic exposure upregulates pulmonary C-fiber NK1R expression to prolong pulmonary C-fiber-mediated apneic response. Toxicol Appl Pharmacol 290:107-15
Lin, Ruei-Lung; Lin, Yu-Jung; Xu, Fadi et al. (2015) Hemorrhagic hypotension-induced hypersensitivity of vagal pulmonary C-fibers to chemical stimulation and lung inflation in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 308:R605-13
Hsu, Chun-Chun; Lee, Lu-Yuan (2015) Role of calcium ions in the positive interaction between TRPA1 and TRPV1 channels in bronchopulmonary sensory neurons. J Appl Physiol (1985) 118:1533-43
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
Lin, Yu-Jung; Lin, Ruei-Lung; Khosravi, Mehdi et al. (2015) Hypersensitivity of vagal pulmonary C-fibers induced by increasing airway temperature in ovalbumin-sensitized rats. Am J Physiol Regul Integr Comp Physiol 309:R1285-91
Lee, Lu-Yuan; Hsu, Chun-Chun; Lin, Yu-Jung et al. (2015) Interaction between TRPA1 and TRPV1: Synergy on pulmonary sensory nerves. Pulm Pharmacol Ther 35:87-93
Hsu, Chun-Chun; Tapia, Reyno J; Lee, Lu-Yuan (2015) Airway extravasation induced by increasing airway temperature in ovalbumin-sensitized rats. Respir Physiol Neurobiol 212-214:46-9
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

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