The goal of this project is to determine the role of neurotrophins in the regulation of neuronal responses that lead to asthma-like symptoms induced by ozone exposure. Neurotrophins, such as nerve growth factor [NGF) and brain-derived neurotrophic factor (BDNF), maintain and regulate neuropeptide and neurotransmitter expression in neurons. Recent studies have shown that neuropeptides and neurotransmitters synthesized and released from airway neurons are important in modulating airway responses to inhaled irritants. The studies in this proposal focus on neurons of airway ganglia. These neurons form the final pathway for both excitatory cholinergic and inhibitory non-adrenergic, non-cholinergic (iNANC) innervation of airway smooth muscle and produce neuropeptides and neurotransmitters that are important regulators of airway and vascular smooth muscle tone, mucous secretion, and mucosal inflammation in the airways. Our studies have demonstrated that NGF enhances substance P (SP) levels in neurons of airway ganglia and increases SP-innervation of cholinergic neurons within the airway. SP enhances airway cholinergic tone by increasing acetylcholine release so regulation of SP synthesis in airway neurons may be important in modulating cholinergic airway responses. Conversely, smooth muscle relaxant mechanisms mediated through iNANC airway nerves may be attenuated through similar neurotrophin signaling pathways. Together, enhanced cholinergic and diminished iNANC influences would lead to airway hyperresponsiveness, as well as increased mucous secretion and airway inflammation. Additional studies are needed to validate hypothesis and elucidate the mechanisms of neurotrophins regulation of cholinergic and iNANC neural pathways of airway neurons. The overall hypothesis of the project is that airway neural responses to inhaled irritants like ozone are mediated through the release of neurotrophins acting on neurotrophin receptors which regulate neurotransmitter or neuropeptide expression in airway neurons.
The specific aims are to: 1) demonstrate that ozone exposure increases neurotrophin synthesis and release by airway epithelium and neurotrophin receptor and NK1 receptor expression in airway neurons;2) determine the direct effects of neurotrophins on cholinergic, iNANC and SP-containing neurons and neurotrophin and NK1 receptors in airway ganglia;3) demonstrate that ozone-induced phenotypic changes in airway neurons result from the actions of neurotrophins. Control of neurotransmitter or neuropeptide production in airway neurons may be critical in airway defensive responses to inhaled irritants, and neurotrophins may contribute to airway hyperresponsiveness and inflammation during asthma exacerbations precipitated by the inhalation of airway irritants and allergens.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Noel, Patricia
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West Virginia University
Schools of Medicine
United States
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Barker, Joshua S; Wu, Zhongxin; Hunter, Dawn D et al. (2015) Ozone exposure initiates a sequential signaling cascade in airways involving interleukin-1beta release, nerve growth factor secretion, and substance P upregulation. J Toxicol Environ Health A 78:397-407
Goravanahally, Madhusudan P; Hubbs, Ann F; Fedan, Jeffery S et al. (2014) Diacetyl increases sensory innervation and substance P production in rat trachea. Toxicol Pathol 42:582-90
Wu, Z-X; Benders, K B; Hunter, D D et al. (2012) Early postnatal exposure of mice to side-steam tobacco smoke increases neuropeptide Y in lung. Am J Physiol Lung Cell Mol Physiol 302:L152-9
Zellner, Leor C; Brundage, Kathleen M; Hunter, Dawn D et al. (2011) Early Postnatal Ozone Exposure Alters Rat Nodose and Jugular Sensory Neuron Development. Toxicol Environ Chem 93:2055-2071
Wu, Zhong-Xin; Hunter, Dawn D; Kish, Vincent L et al. (2009) Prenatal and early, but not late, postnatal exposure of mice to sidestream tobacco smoke increases airway hyperresponsiveness later in life. Environ Health Perspect 117:1434-40
Wu, Z-X; Barker, J S; Batchelor, T P et al. (2008) Interleukin (IL)-1 regulates ozone-enhanced tracheal smooth muscle responsiveness by increasing substance P (SP) production in intrinsic airway neurons of ferret. Respir Physiol Neurobiol 164:300-11
Wu, Z-X; Dey, R D (2006) Nerve growth factor-enhanced airway responsiveness involves substance P in ferret intrinsic airway neurons. Am J Physiol Lung Cell Mol Physiol 291:L111-8
Wilfong, Erin R; Dey, Richard D (2005) The release of nerve growth factor from the nasal mucosa following toluene diisocyanate. J Toxicol Environ Health A 68:1337-48
Wilfong, Erin R; Dey, Richard D (2004) Nerve growth factor and substance P regulation in nasal sensory neurons after toluene diisocyanate exposure. Am J Respir Cell Mol Biol 30:793-800
Wu, Zhong-Xin; Satterfield, Brian E; Dey, Richard D (2003) Substance P released from intrinsic airway neurons contributes to ozone-enhanced airway hyperresponsiveness in ferret trachea. J Appl Physiol 95:742-50

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