| Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. | |
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MedLine Citation:
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PMID: 19106986 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Introduction: Lung injury leads to pulmonary inflammation and fibrosis through myeloid differentiation primary response gene 88 (MyD88) and interleukin-1 receptor 1 (IL-1R1) signalling pathway (J Clin Invest, 2007, 117: 3786-3793). However, the molecular mechanisms by which lung injury triggers IL-1beta production, inflammation and fibrosis remain poorly understood. Based on the fact that cell/tissue injury and necrosis result in production of uric acid, we hypothesised that uric acid crystals formed at the injury site might represent a key danger signal activating the inflammasome to release IL-1beta thereby causing inflammatory lung pathologies. Methods: Mice deficient for MyD88, IL-1R1, NALP3, ASC or Casp-1 on C57Bl/6 genetic background were used. Uric acid concentration was determined in bronchoalveolar lavages and lung homogenates. Bleomycin sulfate (10mg/kg) in saline, uric acid or allopurinol crystals (5-50mg/kg) or saline alone were given through the airways by nasal instillation. The number of cells, chemokines, cytokines and TIMP-1 in the bronchoalveolar space and MPO activity in the lung were evaluated. MMP-2 and MMP-9 levels were determined by gelatin zymography. Results: Here we show that lung injury depends on the NALP3 inflammasome which is triggered by uric acid locally produced in the lung upon bleomycin-induced DNA damage and degradation. Reduction of uric acid levels using the inhibitor of uric acid synthesis allopurinol or uricase lead to a decrease in bleomycin-induced IL- 1beta production, lung inflammation, repair and fibrosis. Further, local administration of exogenous uric acid crystals recapitulates lung inflammation and repair which depend on the NALP3 inflammasome, MyD88 and IL-1R1 pathways, and TLR2 and TLR4 for optimal inflammation, but are independent of the IL-18 receptor. Conclusions: Uric acid released from injured cells constitutes a major endogenous danger signal which activates the NALP3 inflammasome leading to IL-1beta production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1beta production and chronic inflammatory lung pathology. |
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Authors:
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P Gasse; N Riteau; V Pétrilli; J Tschopp; V Lagente; V F J Quesniaux; B Ryffel; I Couillin |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Revue des maladies respiratoires Volume: 25 ISSN: 0761-8425 ISO Abbreviation: - Publication Date: 2008 Nov |
Date Detail:
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Created Date: 2008-12-24 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8408032 Medline TA: Rev Mal Respir Country: France |
Other Details:
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Languages: eng Pagination: 1191 Citation Subset: IM |
Affiliation:
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University of Orleans and CNRS, IEM-UMR6218, Orleans, France. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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