| Macrophages expressing heme oxygenase-1 improve renal function in ischemia/reperfusion injury. | |
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MedLine Citation:
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PMID: 20551909 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Acute kidney injury has a high mortality and lacks specific therapies, with ischemia/reperfusion injury (IRI) being the predominant cause. Macrophages (M phi) have been used successfully in cell therapy to deliver targeted therapeutic genes in models of inflammatory kidney disease. Heme oxygenase-1 (HO-1) catalyzes heme breakdown and has important cytoprotective functions. We hypothesized that administration of M phi modified to overexpress HO-1 would protect from renal IRI. Using an adenoviral construct (Ad-HO-1), HO-1 was overexpressed in primary bone marrow-derived M phi (BMDM). In vitro Ad-HO-1 M phi showed an anti-inflammatory phenotype with increased phagocytosis of apoptotic cells (ACs) and increased interleukin (IL)-10 but reduced TNF-alpha and nitric oxide (NO) following lipopolysaccharide/interferon-gamma (IFN gamma) stimulation compared to control transduced or unmodified M phi. In vivo, intravenously (IV) injected M phi homed preferentially to the post-IRI kidney compared to uninjured control following experimental IRI. At 24 hours postinjury, despite equivalent levels of tubular necrosis, apoptosis, and capillary density between groups, the injection of Ad-HO-1 M phi resulted in preserved renal function (serum creatinine reduced by 46%), and reduced microvascular platelet deposition. These data demonstrate that genetically modified M phi improve the outcomes in IRI when administered after the establishment of structural injury, raising the prospect of targeted cell therapy to support the function of the acutely injured kidney. |
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Authors:
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David A Ferenbach; Vasudev Ramdas; Nishrin Spencer; Lorna Marson; Ignacio Anegon; Jeremy Hughes; David C Kluth |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-15 |
Journal Detail:
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Title: Molecular therapy : the journal of the American Society of Gene Therapy Volume: 18 ISSN: 1525-0024 ISO Abbreviation: Mol. Ther. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-02 Completed Date: 2010-12-22 Revised Date: 2011-09-13 |
Medline Journal Info:
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Nlm Unique ID: 100890581 Medline TA: Mol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 1706-13 Citation Subset: IM |
Affiliation:
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MRC Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, UK. dferenbach@hotmail.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenoviridae
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genetics Animals Apoptosis / genetics, physiology Blotting, Western Fluorescent Antibody Technique Heme Oxygenase-1 / genetics, metabolism* Immunohistochemistry Injections, Intravenous Interferon-gamma / pharmacology Interleukin-10 / metabolism Macrophages / drug effects, metabolism*, physiology Male Mice Reperfusion Injury / genetics, metabolism*, therapy* Tissue Therapy / methods* Tumor Necrosis Factor-alpha / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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G0801235(87702)//Medical Research Council |
| Chemical | |
Reg. No./Substance:
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0/Tumor Necrosis Factor-alpha; 130068-27-8/Interleukin-10; 82115-62-6/Interferon-gamma; EC 1.14.99.3/Heme Oxygenase-1 |
| Comments/Corrections | |
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