Department of Pharmacology, School of Medicine Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
Am J Respir Crit Care Med. 2011 Jan 15;183(2):234-42. doi: 10.1164/rccm.201003-0416OC. Epub 2010 Aug 23.
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.
We investigated the role of the chemokine receptor CCR2 in driving neutrophil infiltration and eliciting tissue damage in remote organs during sepsis.
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.
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.
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.
败血症被定义为感染引起的全身炎症反应，其严重形式与多器官功能障碍综合征（MODS）有关。MODS 发展的确切机制仍不清楚。中性粒细胞在抗感染中起着关键作用；然而，过度激活中性粒细胞会导致组织损伤。
我们研究趋化因子受体 CCR2 在败血症期间驱动中性粒细胞浸润和引发远隔器官组织损伤中的作用。
通过盲肠结扎和穿孔（CLP）模型，用 CCR2 拮抗剂（RS504393）或 CCR2(-/-) 小鼠处理野生型小鼠以诱导败血症。通过髓过氧化物酶活性和荧光激活细胞分选测量器官中的中性粒细胞浸润。通过 Toll 样受体激动剂刺激或从败血症小鼠和患者中分离的中性粒细胞来确定 CCR2 表达和趋化性。
通过 Toll 样受体/核因子-κB 途径依赖的机制，CCR2 表达和对其配体的反应性在 CLP 诱导的败血症期间在循环中性粒细胞中被诱导。CCR2 的遗传或药物抑制可保护小鼠免受 CLP 诱导的死亡。这种保护与肺、心脏和肾脏中的中性粒细胞浸润减少以及血清生化指标的器官损伤和功能障碍减少有关。重要的是，败血症患者的中性粒细胞表达高水平的 CCR2，并且患者疾病的严重程度与中性粒细胞对 CCR2 配体的趋化性增加呈正相关。
总的来说，这些数据确定 CCR2 是一种关键受体，可在败血症期间驱动中性粒细胞不适当浸润远隔器官。因此，CCR2 阻断是治疗败血症诱导的 MODS 的一种新的潜在治疗靶点。
