title: Neurokinin-1 receptor activation induces reactive oxygen species and epithelial damage in allergic airway inflammation.
abstract: BACKGROUND
  An induction of reactive oxygen species (ROS) is characteristic for inflammation but the exact pathways have not been identified for allergic airway diseases so far.
  
  
  OBJECTIVE
  The aim of this study was to characterize the role of the tachykinin NK-1 receptor on ROS production during allergen challenge and subsequent inflammation and remodelling.
  
  
  METHODS
  Precision-cut lung slices of ovalbumin (OVA)-sensitized mice were cultivated and ROS-generation in response to OVA challenge (10 microg/mL) was examined by the 2',7'-dichloroflourescein-diacetate method. Long-term ROS effects on epithelial proliferation were investigated by 5-bromo-2'-deoxyuridine incorporation (72 h). In vivo, the results were validated in OVA-sensitized animals which were treated intra-nasally with either placebo, the tachykinin neurokinin 1 (NK-1) receptor antagonist SR 140333 or the anti-oxidant N-acetylcystein (NAC) before allergen challenge. Inflammatory infiltration and remodelling were assessed 48 h after allergen challenge.
  
  
  RESULTS
  ROS generation was increased by 3.7-fold, which was inhibited by SR 140333. [Sar(9),Met(11)(O(2))]-Substance P (5 nM) caused a tachykinin NK-1 receptor-dependent fourfold increase in ROS generation. Epithelial proliferation was decreased by 68% by incubation with [Sar(9),Met(11)(O(2))]-SP over 72 h. In-vivo, treatment with SR 140333 and NAC reduced epithelial damage (91.4% and 76.8% vs. placebo, respectively, P<0.01) and goblet cell hyperplasia (67.4% and 50.1% vs. placebo, respectively, P<0.05), and decreased inflammatory cell influx (65.3% and 45.3% vs. placebo, respectively, P<0.01).
  
  
  CONCLUSIONS
  Allergen challenge induces ROS in a tachykinin NK-1 receptor-dependent manner. Inhibition of the tachykinin NK-1 receptor reduces epithelial damage and subsequent remodelling in vivo. Therefore, patients may possibly benefit from treatment regime that includes radical scavengers or tachykinin NK-1 receptor antagonists.
authors.affiliation: Department of Cardiology, Division of Applied Cachexia Research, Charité Medical School, Berlin, Germany. jochen.springer@charite.de
authors.forename: J
authors.initials: J
authors.lastname: Springer
authors.forename: D A
authors.initials: DA
authors.lastname: Groneberg
authors.forename: Q T
authors.initials: QT
authors.lastname: Dinh
authors.forename: D
authors.initials: D
authors.lastname: Quarcoo
authors.forename: E
authors.initials: E
authors.lastname: Hamelmann
authors.forename: R C
authors.initials: RC
authors.lastname: Braun-Dullaeus
authors.forename: P
authors.initials: P
authors.lastname: Geppetti
authors.forename: S D
authors.initials: SD
authors.lastname: Anker
authors.forename: A
authors.initials: A
authors.lastname: Fischer
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D006967:Hypersensitivity / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000378:metabolism* / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D017382:Reactive Oxygen Species; D018040:Receptors, Neurokinin-1