Essential Role of CCR2 in Neutrophil Tissue Infiltration and Multiple Organ Dysfunction in Sepsis

Autor(es)

Souto, Fabricio O. ^{[1, 2]} ; Alves-Filho, Jose C. ^{[1, 3]} ; Turato, Walter M. ^[4] ; Auxiliadora-Martins, Maria ^[2] ; Basile-Filho, Anibal ^[2] ; Cunha, Fernando Q. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pharmacol, BR-14049 Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Surg & Anat, BR-14049 Ribeirao Preto - Brazil

^[3] Univ Glasgow, Glasgow Biomed Res Ctr, Div Immunol Infect & Inflammat, Glasgow, Lanark - Scotland

^[4] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049 Ribeirao Preto - Brazil

• Tipo de documento: Artigo Científico
• Fonte: American Journal of Respiratory and Critical Care Medicine; v. 183, n. 2, p. 234-242, JAN 15 2011.
• Citações Web of Science: 63

Resumo

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-kappa B 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. (AU)

• Processo FAPESP: 07/51247-5 - Mediadores envolvidos na gênese da dor e migração de leucócitos e na sepse
• Beneficiário: Sérgio Henrique Ferreira
• Linha de fomento: Auxílio à Pesquisa - Temático