title: Alteration of airway neuropeptide expression and development of airway hyperresponsiveness following respiratory syncytial virus infection.
abstract: The mechanisms by which respiratory syncytial virus (RSV) infection causes airway hyperresponsiveness (AHR) are not fully established. We hypothesized that RSV infection may alter the expression of airway sensory neuropeptides, thereby contributing to the development of altered airway function. BALB/c mice were infected with RSV followed by assessment of airway function, inflammation, and sensory neuropeptide expression. After RSV infection, mice developed significant airway inflammation associated with increased airway resistance to inhaled methacholine and increased tracheal smooth muscle responsiveness to electrical field stimulation. In these animals, substance P expression was markedly increased, whereas calcitonin gene-related peptide (CGRP) expression was decreased in airway tissue. Prophylactic treatment with Sendide, a highly selective antagonist of the neurokinin-1 receptor, or CGRP, but not the CGRP antagonist CGRP(8-37), inhibited the development of airway inflammation and AHR in RSV-infected animals. Therapeutic treatment with CGRP, but not CGRP(8-37) or Sendide, abolished AHR in RSV-infected animals despite increased substance P levels and previously established airway inflammation. These data suggest that RSV-induced airway dysfunction is, at least in part, due to an imbalance in sensory neuropeptide expression in the airways. Restoration of this balance may be beneficial for the treatment of RSV-mediated airway dysfunction.
authors.affiliation: Department of Pediatrics, Division of Cell Biology, National Jewish Medical and Research Center, Denver, CO 80206, USA. dakhamaa@njc.org
authors.forename: Azzeddine
authors.initials: A
authors.lastname: Dakhama
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Gazzar
authors.forename: Taku
authors.initials: T
authors.lastname: Kodama
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Miyahara
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takeda
authors.forename: Arihiko
authors.initials: A
authors.lastname: Kanehiro
authors.forename: Annette
authors.initials: A
authors.lastname: Balhorn
authors.forename: Anthony
authors.initials: A
authors.lastname: Joetham
authors.forename: Joan E
authors.initials: JE
authors.lastname: Loader
authors.forename: Gary L
authors.initials: GL
authors.lastname: Larsen
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000209:etiology; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000821:virology*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology*; D018113:Respiratory Syncytial Virus, Human / Q000472:pathogenicity*; D013373:Substance P / Q000494:pharmacology
chemical_list: D000932:Antiemetics; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D013373:Substance P; C032292:substance P (6-11); D015740:Calcitonin Gene-Related Peptide; D011761:Pyrrolidonecarboxylic Acid