| P2Y6 Receptor Contributes to Airway Inflammation and Remodeling in Experimental Allergic Airway Inflammation. | |
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MedLine Citation:
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PMID: 21512170 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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RATIONALE: Extracellular nucleotides have recently been identified as pro-inflammatory mediators involved in asthma pathogenesis by signaling via purinergic receptors, but the role of the P2Y6R has not been previously investigated. OBJECTIVES: To investigate the role of P2Y6R in asthma pathogenesis. MEASUREMENTS AND MAIN RESULTS: We observed that the intratracheal application of a P2Y6R-antagonist (MRS2578) and P2Y6R deficiency inhibited cardinal features of asthma such as BAL eosinophilia, airway remodeling, Th2 cytokine production, and bronchial hyperresponsiveness in the OVA-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, while intrapulmonary application of the P2Y6R agonist UDP increased the BAL 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. CONCLUSION: 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. |
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Authors:
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Rodolfo Paula Vieira; Tobias Müller; Melanie Grimm; Volker von Gernler; Britta Vetter; Thorsten Dürk; Sanja Cicko; C Korcan Ayata; Stephan Sorichter; Bernard Robaye; Robert Zeiser; Davide Ferrari; Andreas Kirschbaum; Gernot Zissel; J Christian Virchow; Jean-Marie Boeynaems; Marco Idzko |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-21 |
Journal Detail:
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Title: American journal of respiratory and critical care medicine Volume: - ISSN: 1535-4970 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-22 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421642 Medline TA: Am J Respir Crit Care Med Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Pneumology, University Hospital Freiburg, Freiburg, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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