(2s-3s)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine and Respiratory-Syncytial-Virus-Infections

Respiratory syncytial virus (RSV) infection is associated with exaggerated neurogenic inflammation in the airways. This study sought to determine whether irritation of the mucosal sensory fibers affects the recruitment of lymphocytes and monocytes to RSV-infected airways. Pathogen-free rats were inoculated with RSV or with virus-free medium and were injected 5 days later with capsaicin to stimulate airway sensory nerves. Bronchoalveolar lavage was performed 1, 5, or 10 days after nerve stimulation, and samples were analyzed by differential cell count and flow cytometry. Without nerve stimulation, RSV caused a minimal increase in the number of lymphocytes and monocytes above pathogen-free control levels. After nerve stimulation, numerous lymphocytes, predominantly CD4+ T cells, and monocytes were recruited in the airways of infected rats, whereas no difference was found in pathogen-free controls. RSV induced overexpression of the neurokinin 1 (NK1) receptor for substance P on discrete lymphocyte subpopulations within the bronchial-associated lymphoid tissue (BALT), and treatment with a specific NK1 receptor antagonist abolished the recruitment of both lymphocytes and monocytes to infected airways. Our data suggest that airborne irritants stimulating mucosal sensory fibers during RSV infection exert important immunomodulatory effects by attracting to the infected airways selected lymphocyte subpopulations from the local BALT as well as monocytes.

Topics: Adjuvants, Immunologic; Animals; Asthma; Leukocyte Count; Lung; Lymphocyte Subsets; Male; Monocytes; Neurokinin-1 Receptor Antagonists; Neurons, Afferent; Piperidines; Pneumonia, Viral; Rats; Rats, Inbred F344; Receptors, Neurokinin-1; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Specific Pathogen-Free Organisms; Substance P

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.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Cell Line; DNA Primers; Humans; Immunoenzyme Techniques; Lung; Neurogenic Inflammation; Neuropeptides; Piperidines; Rats; Rats, Inbred F344; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Vasoactive Intestinal Peptide; Respiratory Syncytial Virus Infections; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Substance P; Up-Regulation