| Essential Role of CCR2 in Neutrophil Tissue Infiltration and Multiple Organ Dysfunction in Sepsis. | |
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MedLine Citation:
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PMID: 20732989 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Rationale: Sepsis is defined as a systemic inflammatory response to infection, which in its severe form is associated with multiple organ dysfunction syndrome (MODS). The precise mechanisms by which MODS develops remain unclear. Neutrophils have a pivotal role in the defense against infections; however, overwhelming activation of neutrophils is known to elicit tissue damage. Objectives: We investigated the role of the chemokine receptor CCR2 in driving neutrophil infiltration and eliciting tissue damage in remote organs during sepsis. Methods: Sepsis was induced in wild-type mice treated with CCR2 antagonist (RS504393) or CCR2(-/-) mice by cecal ligation and puncture (CLP) model. Neutrophil infiltration into the organs was measured by myeloperoxidase activity and fluorescence-activated cell sorter. CCR2 expression and chemotaxis were determined in neutrophils stimulated with Toll-like receptor agonists or isolated from septic mice and patients. Measurements and Main Results: CCR2 expression and responsiveness to its ligands was induced in circulating neutrophils during CLP-induced sepsis by a mechanism dependent on Toll-like receptor/nuclear factor-κB pathway. Genetic or pharmacologic inhibition of CCR2 protected mice from CLP-induced mortality. This protection was associated with lower infiltration of neutrophils into the lungs, heart, and kidneys and reduced serum biochemical indicators of organ injury and dysfunction. Importantly, neutrophils from septic patients express high levels of CCR2, and the severity of patient illness correlated positively with increasing neutrophil chemotaxis to CCR2 ligands. Conclusions: Collectively, these data identify CCR2 as a key receptor that drives the inappropriate infiltration of neutrophils into remote organs during sepsis. Therefore, CCR2 blockade is a novel potential therapeutic target for treatment of sepsis-induced MODS. |
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Authors:
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Fabricio O Souto; José C Alves-Filho; Walter M Turato; Maria Auxiliadora-Martins; Aníbal Basile-Filho; Fernando Q Cunha |
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Publication Detail:
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Type: Journal Article Date: 2010-08-23 |
Journal Detail:
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Title: American journal of respiratory and critical care medicine Volume: 183 ISSN: 1535-4970 ISO Abbreviation: Am. J. Respir. Crit. Care Med. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421642 Medline TA: Am J Respir Crit Care Med Country: United States |
Other Details:
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Languages: eng Pagination: 234-42 Citation Subset: AIM; IM |
Affiliation:
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Department of Pharmacology, School of Medicine Ribeirao Preto, University of Sao Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirao Preto, Sao Paulo, Brazil. fdqcunha@fmrp.usp.br. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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