Viral infections are known to exacerbate asthma in both adults and children. While a variety of mechanisms are likely to contribute to this effect, neural control of the airways is markedly abnormal in both humans and experimental animals with viral airway infections. Under normal circumstances, the release of acetylcholine from airway vagal fibers is limited by inhibitory M2 muscarinic receptors on the nerve endings. The negative feedback normally provided by these receptors is lost during viral infections. Viral infections can affect M2 receptors via both indirect (inflammatory cell-mediated) and direct (inflammatory cell-independent) mechanisms. Both mechanisms will be further investigated in this project.
Specific aims of this project are:
Specific aim #1 : To determine the mechanisms of virus-induced inflammation of the airway nerves and its role in virus-induced M2 receptor dysfunction. We will investigate the role of interleukin-5, tachykinins, and the interaction of VCAM-1 and VLA-4 in both inflammation of the airway nerves and loss of M2 receptor function. Histology of the airway nerves and functional studies of the M2 receptor will be used as endpoints.
Specific aim #2 : To determine the effects of inflammatory cells and their products on M2 receptor expression and function. Supernatants from activated eosinophils will be added to airway parasympathetic nerves, and the effects on M2 receptor function (determined by measuring stimulated acetylcholine release) and expression will be measured. Interleukin-2 (a cytokine known to affect neurons), interferon-gamma (a product of CD8+ cells responding to viral infections), interleukin-5 (also produced by CD8+ cells in response to virus under certain circumstances), and interleukin-6 (produced by Schwann cells in response to injury; also with effects on neurons) will be tested for effects on similar endpoints. The effects of dexamethasone (which we have shown increases M2 receptor function in vivo), will also be determined.
Specific aim #3 : To determine the direct effects of viral infection on M2 receptor expression and function. Cultured nerve cells will be infected with parainfluenza virus and the effects on effects on M2 receptor function and expression will be measured. Because oxygen radicals can be important intermediates in virus-induced gene expression, we will study the effects of antioxidants on virus-induced changes in M2 receptor expression and function. The direct effects of neuraminidase on M2 receptor function will also be tested, as we have shown that viral neuraminidase decreases M2 receptor agonist affinity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054659-04
Application #
6125777
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1996-12-20
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
4
Fiscal Year
2000
Total Cost
$271,292
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Drake, Matthew G; Evans, Scott E; Dickey, Burton F et al. (2013) Toll-like receptor-2/6 and Toll-like receptor-9 agonists suppress viral replication but not airway hyperreactivity in guinea pigs. Am J Respir Cell Mol Biol 48:790-6
Verhein, Kirsten C; Salituro, Francesco G; Ledeboer, Mark W et al. (2013) Dual p38/JNK mitogen activated protein kinase inhibitors prevent ozone-induced airway hyperreactivity in guinea pigs. PLoS One 8:e75351
Nie, Zhenying; Fryer, Allison D; Jacoby, David B (2012) ?2-Agonists inhibit TNF-?-induced ICAM-1 expression in human airway parasympathetic neurons. PLoS One 7:e44780
Buels, Kalmia S; Fryer, Allison D (2012) Muscarinic receptor antagonists: effects on pulmonary function. Handb Exp Pharmacol :317-41
Kaufman, Elad H; Fryer, Allison D; Jacoby, David B (2011) Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs. J Allergy Clin Immunol 127:462-9
Moreno-Vinasco, Liliana; Verbout, Norah G; Fryer, Allison D et al. (2009) Retinoic acid prevents virus-induced airway hyperreactivity and M2 receptor dysfunction via anti-inflammatory and antiviral effects. Am J Physiol Lung Cell Mol Physiol 297:L340-6
Verbout, Norah G; Jacoby, David B; Gleich, Gerald J et al. (2009) Atropine-enhanced, antigen challenge-induced airway hyperreactivity in guinea pigs is mediated by eosinophils and nerve growth factor. Am J Physiol Lung Cell Mol Physiol 297:L228-37
Hackett, Tillie-Louise; Shaheen, Furquan; Johnson, Andrew et al. (2008) Characterization of side population cells from human airway epithelium. Stem Cells 26:2576-85
Verhein, Kirsten C; Jacoby, David B; Fryer, Allison D (2008) IL-1 receptors mediate persistent, but not acute, airway hyperreactivity to ozone in guinea pigs. Am J Respir Cell Mol Biol 39:730-8
Proskocil, Becky J; Bruun, Donald A; Lorton, Jesse K et al. (2008) Antigen sensitization influences organophosphorus pesticide-induced airway hyperreactivity. Environ Health Perspect 116:381-8

Showing the most recent 10 out of 38 publications