There is a fundamental gap in understanding how local inflammation in the airways perverts vagal sensory C-fiber function, resulting in excessive and chronic cough, dyspnea, mucus secretion and bronchospasm in airway diseases including asthma, viral exacerbations and COPD. Consequently, there are no treatments available that are more effective than placebo at reducing these debilitating neuronal responses. C-fiber terminals in the airways are densely packed with mitochondria. Furthermore inflammatory signaling causes reactive oxygen species (ROS) production from the mitochondrial electron transport chain. Preliminary data indicates that modulation of the nerve terminal mitochondrial electron transport chain causes ROS-dependent (i) C-fiber activation and (ii) increased C-fiber excitability (hyperexcitability). The central hypothesis is that sensory terminal mitochondria function as an integrated transduction mechanism that converts inflammatory signaling into intraneuronal ROS, which potently increase electrical activity. The hypothesis is innovative because it will, for the first time, identify nerve terminal mitochondria as critical initiators of excessive C-fiber- associated symptoms in airway disease. The contribution of this study is expected to be a complete understanding of the mechanisms involved in the activation and hyperexcitability of airway C-fibers following mitochondrial modulation and its contribution to inflammation-induced hyperreflexia in vivo. Based on strong preliminary data, the hypothesis will be tested by pursing three specific aims: (1) Determine the mechanism by which modulation of the mitochondrial electron transport chain activates airway C-fibers. It is hypothesized that this activation is dependent on transient receptor potential ankyrin 1 (TRPA1) channel activation by mitochondrially-derived ROS. (2) Identify the mechanism underlying the hyperexcitability of airway C-fibers following modulation of the mitochondrial electron transport chain. It is hypothesized that this hyperexcitability is via ROS-mediated PKC? modulation of voltage-gated Na+ channels. (3) Determine the contribution of oxidative stress in airway sensory nerve terminals to in vivo hyperreflexia in a murine ovalbumin model of allergic asthma. It is hypothesized that allergic inflammation in the lung causes excessive airway reflexes due to mitochondrial ROS production in airway sensory nerve terminals. This study is significant because it is an absolute requirement for understanding the causal link between inflammation and the debilitating neuronal responses of cough, dyspnea, hypersecretion and bronchospasm. Mitochondria represent a potential bottleneck between multiple parallel inflammatory signaling pathways and aberrant sensory nerve activity. The approach is innovative because mechanisms will be studied directly at the C-fiber terminal using novel electrophysiological and isolation techniques. Thus these studies will have a transformative impact upon our understanding of aberrant C-fiber function during inflammation, and are expected to identify novel therapeutic targets for the treatment of inflammatory airway diseases such as asthma, viral exacerbations and COPD.

Public Health Relevance

The proposed research is relevant to public health because the identification of the mechanisms underlying the excessive cough and other reflexes evoked by lung inflammation is ultimately expected to lead to the development of novel therapeutic lines for the treatment of airway disease. Thus, the proposed research is relevant to NHLBI's mission to reduce morbidities and health care costs caused by asthma and other airway diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Noel, Patricia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of South Florida
Schools of Medicine
United States
Zip Code
Hooper, J S; Hadley, S H; Morris, K F et al. (2016) Characterization of cardiovascular reflexes evoked by airway stimulation with allylisothiocyanate, capsaicin, and ATP in Sprague-Dawley rats. J Appl Physiol (1985) 120:580-91
Bahia, Parmvir K; Parks, Thomas A; Stanford, Katherine R et al. (2016) The exceptionally high reactivity of Cys 621 is critical for electrophilic activation of the sensory nerve ion channel TRPA1. J Gen Physiol 147:451-65
Taylor-Clark, Thomas E (2016) Role of reactive oxygen species and TRP channels in the cough reflex. Cell Calcium 60:155-62
Taylor-Clark, Thomas E (2015) Peripheral neural circuitry in cough. Curr Opin Pharmacol 22:9-17
Taylor-Clark, Thomas E (2015) Oxidative stress as activators of sensory nerves for cough. Pulm Pharmacol Ther 35:94-9
Taylor-Clark, Thomas E; Wu, Kevin Y; Thompson, Julie-Ann et al. (2015) Thy1.2 YFP-16 transgenic mouse labels a subset of large-diameter sensory neurons that lack TRPV1 expression. PLoS One 10:e0119538
Undem, Bradley J; Taylor-Clark, Thomas (2014) Mechanisms underlying the neuronal-based symptoms of allergy. J Allergy Clin Immunol 133:1521-34
Hadley, Stephen H; Bahia, Parmvir K; Taylor-Clark, Thomas E (2014) Sensory nerve terminal mitochondrial dysfunction induces hyperexcitability in airway nociceptors via protein kinase C. Mol Pharmacol 85:839-48
Nesuashvili, Lika; Hadley, Stephen H; Bahia, Parmvir K et al. (2013) Sensory nerve terminal mitochondrial dysfunction activates airway sensory nerves via transient receptor potential (TRP) channels. Mol Pharmacol 83:1007-19