| PPARγ activation normalizes resolution of acute sterile inflammation in murine chronic granulomatous disease. | |
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MedLine Citation:
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PMID: 20693431 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Absence of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase predisposes chronic granulomatous disease (CGD) patients to infection, and also to unexplained, exaggerated inflammation. The impaired recognition and removal (efferocytosis) of apoptotic neutrophils by CGD macrophages may contribute to this effect. We hypothesized that peroxisome proliferator-activated receptor γ (PPARγ) activation during CGD inflammation is deficient, leading to altered macrophage programming and decreased efferocytosis, and that PPARγ agonism would enhance resolution. using the gp91(phox-/-) murine model of X-linked CGD in a well-characterized model of sterile, zymosan-induced peritonitis, it was demonstrated that PPARγ expression and activation in CGD macrophages were significantly deficient at baseline, and acquisition was delayed over the course of inflammation relative to that of wild-type. Efferocytosis by macrophages reflected PPARγ activation during peritonitis and was impaired in CGD mice (versus wild-type), leading to accumulation of apoptotic neutrophils. Importantly, provision of the PPARγ agonist, pioglitazone, either prophylactically or during inflammation, significantly enhanced macrophage PPARγ-mediated programming and efferocytosis, reduced accumulation of apoptotic neutrophils, and normalized the course of peritonitis in CGD mice. As such, PPARγ may be a therapeutic target for CGD, and possibly other inflammatory conditions where aberrant macrophage programming and impaired efferocytosis delay resolution of inflammation. |
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Authors:
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Ruby Fernandez-Boyanapalli; S Courtney Frasch; David W H Riches; R William Vandivier; Peter M Henson; Donna L Bratton |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-08-06 |
Journal Detail:
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Title: Blood Volume: 116 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-26 Completed Date: 2011-01-13 Revised Date: 2012-04-04 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 4512-22 Citation Subset: AIM; IM |
Affiliation:
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Department of Pediatrics, National Jewish Health, Denver, CO, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cytokines / immunology Gene Deletion Gene Expression Regulation / drug effects Granulomatous Disease, Chronic / complications*, drug therapy*, immunology Humans Inflammation / chemically induced, complications, drug therapy, immunology Macrophages / drug effects, immunology, metabolism Male Membrane Glycoproteins / genetics Mice Mice, Inbred C57BL NADPH Oxidase / genetics Neutrophils / drug effects PPAR gamma / agonists*, genetics, immunology* Peritonitis / chemically induced, complications*, drug therapy*, immunology Thiazolidinediones / therapeutic use* Zymosan |
| Grant Support | |
ID/Acronym/Agency:
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A1058228//PHS HHS; GM61031/GM/NIGMS NIH HHS; HL34303/HL/NHLBI NIH HHS; HL68864/HL/NHLBI NIH HHS; HL81151/HL/NHLBI NIH HHS; R01 HL068864-09/HL/NHLBI NIH HHS; R01 HL081151-07/HL/NHLBI NIH HHS; R01 HL081151-08/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Membrane Glycoproteins; 0/PPAR gamma; 0/Thiazolidinediones; 111025-46-8/pioglitazone; 9010-72-4/Zymosan; EC 1.6.3.1/Cybb protein, mouse; EC 1.6.3.1/NADPH Oxidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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