title: Purinergic receptor type 6 contributes to airway inflammation and remodeling in experimental allergic airway inflammation.
abstract: BACKGROUND
  Extracellular nucleotides have recently been identified as proinflammatory mediators involved in asthma pathogenesis by signaling via purinergic receptors, but the role of the purinergic receptor type 6 (P2Y6R) has not been previously investigated.
  
  
  OBJECTIVE
  To investigate the role of P2Y6R in asthma pathogenesis.
  
  
  METHODS
  Acute and chronic OVA model and also HDM model of allergic inflammation in C57Bl/6 mice treated with specific P2Y6R antagonist and P2Y6R(-/-) mice were evaluated for classical features of asthmatic inflammation. In addition, primary epithelial cell culture from human and epithelial cell lines from mouse and human were stimulated with P2Y6R agonist and treated with P2Y6R antagonist and assessed for IL-6, IL-8/CXCL8 and KC levels. Experiments with P2Y6R(-/-) and P2Y6R(+/+) chimera were performed to discriminate the role of P2Y6R activation in structural lung cells and in cells from hematopoietic system.
  
  
  RESULTS
  We observed that the intratracheal application of a P2Y6R antagonist (MRS2578) and P2Y6R deficiency inhibited cardinal features of asthma, such as bronchoalveolar lavage eosinophilia, airway remodeling, Th2 cytokine production, and bronchial hyperresponsiveness in the ovalbumin-alum model. MRS2578 was also effective in reducing airway inflammation in a model using house dust mite extracts to induce allergic lung inflammation. Experiments with bone marrow chimeras revealed the importance of the P2Y6R expression on lung structural cells in airway inflammation. In accordance with this finding, we found a strong up-regulation of P2Y6 expression on airway epithelial cells of animals with experimental asthma. Concerning the underlying mechanism, we observed that MRS2578 inhibited the release of IL-6 and IL-8/KC by lung epithelial cells in vivo, whereas intrapulmonary application of the P2Y6R agonist uridine-5'-diphosphate increased the bronchoalveolar levels of IL-6 and KC. In addition, selective activation of P2Y6 receptors induced the release of IL-6 and KC/IL-8 by murine and human lung epithelial cells in vitro.
  
  
  CONCLUSIONS
  P2Y6R expression on airway epithelial cells is up-regulated during acute and chronic allergic airway inflammation, and selective blocking of P2Y6R or P2Y6R deficiency on the structural cells reduces cardinal features of experimental asthma. Thus, blocking pulmonary P2Y6R might be a target for the treatment of allergic airway inflammation.
authors.affiliation: University Hospital Freiburg, Department of Pneumology, Freiburg, Germany.
authors.forename: Rodolfo Paula
authors.initials: RP
authors.lastname: Vieira
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Melanie
authors.initials: M
authors.lastname: Grimm
authors.forename: Volker
authors.initials: V
authors.lastname: von Gernler
authors.forename: Britta
authors.initials: B
authors.lastname: Vetter
authors.forename: Thorsten
authors.initials: T
authors.lastname: Dürk
authors.forename: Sanja
authors.initials: S
authors.lastname: Cicko
authors.forename: C Korcan
authors.initials: CK
authors.lastname: Ayata
authors.forename: Stephan
authors.initials: S
authors.lastname: Sorichter
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.forename: Davide
authors.initials: D
authors.lastname: Ferrari
authors.forename: Andreas
authors.initials: A
authors.lastname: Kirschbaum
authors.forename: Gernot
authors.initials: G
authors.lastname: Zissel
authors.forename: J Christian
authors.initials: JC
authors.lastname: Virchow
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
mesh_terms: D056151:Airway Remodeling / Q000276:immunology*; D000534:Alum Compounds; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008168:Lung / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin; D011983:Receptors, Purinergic / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000276:immunology*
chemical_list: D000534:Alum Compounds; D016207:Cytokines; D011983:Receptors, Purinergic; C446402:ovalbumin-alum; D010047:Ovalbumin