Viral infections such as influenza are characterized by an increased bronchoconstriction to a variety of stimuli in vivo. Although this hyperreactivity is usually temporary, viral infections in childhood are associated with development of asthma. The hyperreactivity to any specific agonist could result from direct effects on smooth muscle or effects on cells that control smooth muscle contraction. A major indirect route of hyperreactivity Is via the vagus nerve. The vagus nerve releases acetylcholine that binds to muscarinic receptors on the smooth muscle resulting in bronchoconstriction. In preliminary data I have shown that the amount of acetylcholine released by the nerve terminals is regulated by muscarinic receptors which are located on the nerve terminals, and that these neuronal receptors are a different subtype than the muscarinic receptors on the smooth muscle. The neuronal muscarinic receptors are inhibitory in that when stimulated, they limit the amount of acetylcholine released from the nerves. Damage to these neuronal receptors would remove both the tonic inhibition and the negative feedback that occurs with all stimuli which increase vagal activity. It is my hypothesis that the pathologic absence of this normal negative feedback will result in airways hyperreactivity. Viral infections such as influenza and parainfluenza, temporarily increases the bronchoconstriction produced by a variety of stimuli. The mechanism of viral-induced airway hyperreactivity is poorly understood. However, there is evidence to suggest that part of the defect lies in the vagus nerves. Viruses contain enzymes on their surface which can damage cells and receptors on cells. One of these enzymes, neuraminidase, can damage receptors like the muscarinic receptor which inhibits acetylcholine release from the vagus nerves in the lung. Neuraminidase may be produced in large quantities during viral infection as new viruses grow in the airways. I have shown that during viral infection neuronal inhibitory muscarinic receptors are not functioning. The experiments in this proposal are designed to test whether damage to these receptors on the vagus nerves play an important role in the reactivity of the lungs, whether this effect is due specifically to inhibition of neuronal muscarinic receptors by neuraminidase, and what role neuraminidase plays in other models of airways disease, especially antigen challenge. This grant proposes studying muscarinic receptor function in vivo and in vitro as well as studying the receptors at a genetic level. It is expected that results from this study will provide important new insights into the mechanism of airway hyperreactivity induced by viral infection and may yield results which further our understanding of other models of airway disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Pathology A Study Section (PTHA)
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Johns Hopkins University
Public Health & Prev Medicine
Schools of Public Health
United States
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