Abstract

Eosinophils cluster around airway nerves in patients with asthma. This physical interaction of eosinophils and airway nerves is central to virus induced dysfunction of inhibitory M2 muscarinic receptors and airway hyperreactivity in antigen sensitized hosts. We hypothesize that eosinophils are attracted to nerves by chemokines produced by the nerve cells, and that the eosinophils are anchored to the nerves by adhesion molecules, which facilitate their activation. We will investigate these interactions using an in vivo model of the interaction of antigen sensitization with viral infection, and will also undertake in vitro studies using primary cultures of human airway parasympathetic neurons, as well as guinea pig airway neurons and human neuroblastoma cells. We propose the following specific aims:
SPECIFIC AIM #1 : To determine the effects of blocking the CCR3 receptor, as well as ICAM-1 and VCAM, on recruitment of eosinophils to the airway nerves in vivo, and on the physiological responses to viral infection in naive and sensitized animals.
SPECIFIC AIM #2 : To determine the regulation of eotaxin as well as other CCR3 ligands), ICAM-1, and VCAM expression in primary cultures of human and guinea pig airway parasympathetic neurons and in human neuroblastoma cells. Regulation by TH2 cytokines IL4, IL5, and IL13 (expected to be important in the response to allergen sensitization) and by TNFa, and the interactions of these with interferon? (produced in response to viral infections) will be studied, as well as the effects of dexamethasone treatment.
SPECIFIC AIM #3 : To investigate the role of NF-?B and STAT-6 in regulating the expression of eotaxin by airway parasympathetic neurons.
SPECIFIC AIM #4 : To test the effects of blocking TNFa on the response to viral infections in sensitized animals. Effects on eosinophil recruitment to airway nerves, eosinophil activation, airway hyperreactivity, M2 muscarinic receptor dysfunction, and the neural expression of chemokines and adhesion molecules will be studied. This work is highly relevant to understanding how viral infections cause asthma attacks. In the course of these experiments, substances released by lung cells that contribute to asthma will be identified, and ways to block them will be tested. This will assist us in developing new treatments for asthma.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061013-09
Application #
7596898
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
1998-07-10
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
9
Fiscal Year
2009
Total Cost
$231,000
Indirect Cost

  Institution

Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239

  Publications

Rynko, Abby E; Fryer, Allison D; Jacoby, David B (2014) Interleukin-1? mediates virus-induced m2 muscarinic receptor dysfunction and airway hyperreactivity. Am J Respir Cell Mol Biol 51:494-501
Buels, K S; Jacoby, D B; Fryer, A D (2012) Non-bronchodilating mechanisms of tiotropium prevent airway hyperreactivity in a guinea-pig model of allergic asthma. Br J Pharmacol 165:1501-14
Koguchi, Yoshinobu; Buenafe, Abigail C; Thauland, Timothy J et al. (2012) Preformed CD40L is stored in Th1, Th2, Th17, and T follicular helper cells as well as CD4+ 8- thymocytes and invariant NKT cells but not in Treg cells. PLoS One 7:e31296
Foster, Erin L; Simpson, Eric L; Fredrikson, Lorna J et al. (2011) Eosinophils increase neuron branching in human and murine skin and in vitro. PLoS One 6:e22029
Verhein, Kirsten C; Hazari, Mehdi S; Moulton, Bart C et al. (2011) Three days after a single exposure to ozone, the mechanism of airway hyperreactivity is dependent on substance P and nerve growth factor. Am J Physiol Lung Cell Mol Physiol 300:L176-84
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
Hays, L E; Zodrow, D M; Yates, J E et al. (2008) Cigarette smoke induces genetic instability in airway epithelial cells by suppressing FANCD2 expression. Br J Cancer 98:1653-61
Hackett, Tillie-Louise; Shaheen, Furquan; Johnson, Andrew et al. (2008) Characterization of side population cells from human airway epithelium. Stem Cells 26:2576-85
Wong, John; Korcheva, Veselina; Jacoby, David B et al. (2007) Proinflammatory responses of human airway cells to ricin involve stress-activated protein kinases and NF-kappaB. Am J Physiol Lung Cell Mol Physiol 293:L1385-94

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