Respiratory Syncytial Virus (RSV) is the most important respiratory pathogen in infancy and early childhood. Infection with this virus is associated with airway inflammation and hyperreactivity whose mechanisms remain unclear. In preliminary studies, we found that RSV makes rat airways abnormally susceptible to neurogenic-mediated inflammation, as manifested by an unusually large extravasation of albumin in response to sensory nerve stimulation. Surprisingly, the peptide-degrading activity of the regulatory enzyme neutral endopeptidase was unchanged in RSV-infected rats, indicating that the mechanism of RSV-induced potentiation is different from that suggested for other respiratory viruses (influenza, parainfluenza). Instead, we found evidence that RSV causes strong upregulation of the gene coding for the high-affinity substance P receptor (NK1), which translates into a large increase in the number of these receptors expressed in the airway mucosa. Furthermore, our data indicate that the potentiation of neurogenic-mediated inflammation in RSV- infected airways is a long-lasting phenomenon, and that the neurogenic responses to RSV in weanling rats are different from adult rats. On the basis of these preliminary observations, we hypothesize that potentiation of neurogenic inflammation is an important early event in RSV-infected lungs leading to acute pulmonary inflammation and to subsequent development of persistent airway hyperreactivity, and that the primary mechanism of these effects is the abnormal expression of neuropeptide receptors. Secondly, we hypothesize that RSV infections occurring in the early postnatal period cause persistent modifications in the neurogenic inflammatory pathways predisposing to airway inflammation and hyperreactivity throughout infancy and possibly adulthood. The following specific aims are organized around the evaluation of these hypotheses: 1) To study the influence of RSV on the expression of neuropeptide receptors and to assess the time course of chronic neuropeptide-mediated bronchovascular and bronchomotor effects after an acute RSV infection in adult animals; and 2) To determine whether RSV infections occurring in the early post- natal period affect the expression of neuropeptide receptors differently from infections occurring in adulthood and whether they can cause permanent potentiation of the neurogenic bronchovascular and bronchomotor responses. These studies may provide important information concerning the mechanisms of post- RSV childhood asthma.
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