The long-range goal in this project is to identify neural mechanisms involved in airway responses to inhaled irritants. Recent studies have shown enhanced neuropeptide and neurotransmitter synthesis after allergic injury or irritant exposure to the airways. There is increasing evidence that cytokines and growth factors released during inflammation in the airways mediate neuronal responses. We propose to study the time course, including up regulation and recovery, of neurotransmitter expression in sensory and intrinsic airway neurons and changes in airway smooth muscle responsiveness after ozone exposure. We will evaluate the role of nerve growth factors and inflammatory cytokines that contribute to the induction, maintenance and recovery of airway neurons and identify mechanisms involved in regulating neuronal and airway responses to inhaled irritants such as ozone.
The specific aims are: 1) to establish the time course of neuronal changes and airway function during the initial inflammatory response to and subsequent recovery from single or repeated ozone exposures; 2) to identify specific neural pathways involved in altered airway responses after ozone exposure; 3) to evaluate the airway neuronal, inflammatory and smooth muscle responses to specific cytokines and growth factors, initially IL-1, LIF and NGF; and 4) to identify the role of cytokines and growth factors in regulating neuronal and airway responses to ozone exposure. These experiments will determine mechanisms of neural responses to irritant exposures like ozone and evaluate the role of cytokines and growth factors regulating ozone-induced neurotransmitter expression of intrinsic and sensory airway neurons. Better understanding of neural responses in the airways may lead to new ways of controlling and treating asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035812-12
Application #
6638257
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Noel, Patricia
Project Start
1986-12-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
12
Fiscal Year
2003
Total Cost
$182,500
Indirect Cost
Name
West Virginia University
Department
Biology
Type
Schools of Medicine
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
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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