Viral infections can be identified in as many as 80 percent of children during asthma attacks. While a variety of mechanisms may contribute to this effect, neural control of the airways is markedly abnormal in both humans and experimental animals under these conditions. 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, increasing acetylcholine release and reflex bronchoconstriction. M2 receptor dysfunction can occur via several mechanisms, some of which are dependent upon the inflammatory response to the virus. Although the inflammatory response to viral infections is typically characterized by neutrophils and mononuclear cells, this may vary depending on the atopic status of the host. As many asthmatics are also atopic, the inflammatory response to viral infection may involve an influx of eosinophils into the airways, as well as production of interleukin-5 by both CD4+ and CD8+ T-lymphocytes. It has been previously demonstrated that the eosinophil is responsible for M2 receptor dysfunction after inhalation of allergen. In contrast, in virus-infected animals, the eosinophil is not responsible for loss of M2 receptor function. This project will investigate the role of the eosinophil in M2 receptor dysfunction during viral infections in guinea pigs sensitized to a non-viral antigen (ovalbumin). It is hypothesized that in sensitized guinea pigs, viral infection will result in recruitment of eosinophils to airway nerves, eosinophil activation, release of major basic protein, loss of M2 receptor function, increased release of acetylcholine and hyperreactivity.
The specific aims are designed to examine 1) whether loss of M2 receptor function in sensitized, virus infected animals is mediated via eosinophils, 2) what inflammatory mediators are required for recruiting eosinophils to the airway nerves in these animals, 3) what role CD4+ and CD8+ T-lymphocytes play in recruiting eosinophils, and 4) what effect eosinophil proteins have on neuronal M2 receptor functional.
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