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.
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