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.
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