Respiratory syncytial virus (RSV) is a major respiratory pathogen in infants. The first goal of this study was to determine whether the infection following endotracheal inoculation of RSV in Fischer 344 rats results in increased inflammatory responses to substance P (SP) either released by capsaicin from sensory nerves or injected into the circulation. Five days after inoculation, the extravasation of Evans blue-labeled albumin after capsaicin or SP was significantly greater in RSV-infected airways than in pathogen-free controls. The peptide-degrading activity of the regulatory enzyme neutral endopeptidase was unaffected by RSV. However, SP(NK(1)) receptor mRNA levels increased fivefold in RSV-infected lungs, and the density of SP binding sites in the bronchial mucosa increased threefold. These data suggest that RSV makes the airways abnormally susceptible to the proinflammatory effects of SP by upregulating SP(NK(1)) receptor gene expression, thereby increasing the density of these receptors on target cells. This effect may contribute to the inflammatory reaction to the virus and could be a target for the therapy of RSV disease and its sequelae.

Respiratory syncytial virus (RSV) infection in adult rats causes exaggerated inflammation after sensory nerve stimulation in the extrapulmonary, but not in the intrapulmonary airways. The goal of this study was to analyze neurogenic inflammation in weanling F-344 rats infected with RSV 18 +/- 2 d after birth. Five days after RSV inoculation, the extravasation of Evans blue-labeled albumin after nerve stimulation was significantly greater in the intrapulmonary airways of RSV-infected weanling rats than in pathogen-free control rats. In contrast, no difference was found in the extrapulmonary airways. The level of messenger RNA (mRNA) encoding the substance P (SP) receptor (neurokinin 1 [NK1]) increased fourfold in RSV-infected lungs, whereas mRNA encoding the VIPR1 receptor for the antiinflammatory vasoactive intestinal peptide (VIP) increased to a much lesser degree. mRNAs encoding the other neurokinin (NK2) and VIP (VIPR2) receptors were not affected by the virus. Selective inhibition of the NK1 receptor abolished neurogenic inflammation in RSV-infected intrapulmonary airways. Also, neurogenic inflammation and NK1 receptor upregulation in infected lungs were inhibited by prophylaxis with a monoclonal antibody against RSV. These data suggest that RSV lower respiratory tract infection makes the intrapulmonary airways of young rats abnormally susceptible to the proinflammatory effects of SP by selectively upregulating the expression of NK1 receptors.

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