EXCEED THE SPACE PROVIDED. The incidence of asthma has increased dramatically in industrialized countries over the last 20 years. Currently approximately 17 million people have been diagnosed with asthma in the U.S. Epidemiological and human clinical studies have shown that inhalation of the photochemical air pollutant ozone exacerbates asthma. This exacerbation can be characterized by two responses. First, asthmatics have been shown to have greater pulmonary function decrements, symptoms and airway inflammation when acutely exposed to ozone. Second, the acute inhalation of ozone has been shown to increase the responsiveness to an inhaled allergen in patients with atopic asthma. The underlying mechanisms involved in these ozone-asthma interactions remain undefined. We hypothesize that these ozone-asthma interactions are mediated by either reflex responses involving the central nervous system or the release of neuropeptides from afferent nerve endings located in the airway. To test this hypothesis we have devised the following four specific aims:
Specific Aim 1, In Brown-Norway rats sensitized and challenged with ovalbumin, we will determine which group of lung vagal afferents (myleinated vs. nonmyleinated) contribute to the airway responses associated with ozone-asthma interactions by blocking vagal C-fiber conduction with perineural capsaicln treatment and then combining the C-fiber block with cold block of mylenated vagal fibers.
Specific Aim 2, using single nerve fiber recording techniques we will examine the discharge pattern of vagal afferent fibers following an acute inhalation of ozone in Brown-Norway rats that have been sensitized and challenged with ovalbumin and during a subsequent allergen aerosol challenge.
Specific Aim 3, we will examine the influence that the neuropeptides, substance P (SP) and calcitonin gene related peptide (CGRP) have on the migration of and cytokine production from inflammatory/immunecells and epithelial cells.
Specific Aim 4, we will examine the role of SP, CGRP and vasoactive intestinal peptide (VIP) in airway epithelial and lymph node proliferative responses following an acute inhalation of ozone in normal and ovalbumin sensitized and challenged rats. The information obtained from these studies will help define the ozone-asthma mechanisms that lung sensory nerves mediate during acute exposure to ozone in allergen sensitized animals and may provide insight into basic mechanisms that influence diseases that involve airway epithelial injury. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES006791-09
Application #
6839481
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Tinkle, Sally S
Project Start
1996-06-04
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2006-12-31
Support Year
9
Fiscal Year
2005
Total Cost
$297,000
Indirect Cost
Name
University of California Davis
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Schelegle, Edward S; Walby, William F (2012) Vagal afferents contribute to exacerbated airway responses following ozone and allergen challenge. Respir Physiol Neurobiol 181:277-85
Oslund, Karen L; Hyde, Dallas M; Putney, Leialoha F et al. (2008) Activation of neurokinin-1 receptors during ozone inhalation contributes to epithelial injury and repair. Am J Respir Cell Mol Biol 39:279-88
Mansoor, Jim K; Decile, Kendra C; Giri, Shri N et al. (2007) Influence of pirfenidone on airway hyperresponsiveness and inflammation in a Brown-Norway rat model of asthma. Pulm Pharmacol Ther 20:660-8
Alfaro, Mario F; Putney, Lei; Tarkington, Brian K et al. (2004) Effect of rapid shallow breathing on the distribution of 18O-labeled ozone reaction product in the respiratory tract of the rat. Inhal Toxicol 16:77-85
Larson, Shawnessy D; Plopper, Charles G; Baker, Greg et al. (2004) Proximal airway mucous cells of ovalbumin-sensitized and -challenged Brown Norway rats accumulate the neuropeptide calcitonin gene-related peptide. Am J Physiol Lung Cell Mol Physiol 287:L286-95
Larson, Shawnessy D; Schelegle, Edward S; Walby, William F et al. (2004) Postnatal remodeling of the neural components of the epithelial-mesenchymal trophic unit in the proximal airways of infant rhesus monkeys exposed to ozone and allergen. Toxicol Appl Pharmacol 194:211-20
Schelegle, E S; Alfaro, M F; Putney, L et al. (2001) Effect of C-fiber-mediated, ozone-induced rapid shallow breathing on airway epithelial injury in rats. J Appl Physiol 91:1611-8
Schelegle, E S; Eldridge, M W; Cross, C E et al. (2001) Differential effects of airway anesthesia on ozone-induced pulmonary responses in human subjects. Am J Respir Crit Care Med 163:1121-7
Sterner-Kock, A; Braun, R K; van der Vliet, A et al. (1999) Substance P primes the formation of hydrogen peroxide and nitric oxide in human neutrophils. J Leukoc Biol 65:834-40
Vesely, K R; Schelegle, E S; Stovall, M Y et al. (1999) Breathing pattern response and epithelial labeling in ozone-induced airway injury in neutrophil-depleted rats. Am J Respir Cell Mol Biol 20:699-709