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首页> 美国卫生研究院文献>PLoS Pathogens >Scavenger Receptor Class A Plays a Central Role in Mediating Mortality and the Development of the Pro-Inflammatory Phenotype in Polymicrobial Sepsis
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Scavenger Receptor Class A Plays a Central Role in Mediating Mortality and the Development of the Pro-Inflammatory Phenotype in Polymicrobial Sepsis

机译：清除剂受体A类在介导死亡率和多发性脓毒症中促炎表型的发展中起着核心作用

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Sepsis is a frequent complication in critical illness. The mechanisms that are involved in initiation and propagation of the disease are not well understood. Scavenger receptor A (SRA) is a membrane receptor that binds multiple polyanions such as oxidized LDL and endotoxin. Recent studies suggest that SRA acts as a pattern recognition receptor in the innate immune response. The goal of the present study was to determine the role of SRA in polymicrobial sepsis. SRA deficient (SRA−/−) and C57BL/6JB/6J (WT) male mice were subjected to cecal ligation and puncture (CLP) to induce polymicrobial sepsis. NFκB activity, myeloperoxidase activity, and co-association of SRA with toll like receptor (TLR) 4 and TLR2 was analyzed in the lungs. Spleens were analyzed for apoptosis. Serum cytokines and chemokines were assayed. Blood and peritoneal fluid were cultured for aerobic and anaerobic bacterial burdens. Long term survival was significantly increased in SRA−/− septic mice (53.6% vs. 3.6%, p<0.05) when compared to WT mice. NFκB activity was 45.5% lower in the lungs of SRA−/− septic mice versus WT septic mice (p<0.05). Serum levels of interleukin (IL)-5, IL-6, IL-10 and monocyte chemoattractant protein −1 were significantly lower in septic SRA−/− mice when compared to septic WT mice (p<0.05). We found that SRA immuno-precipitated with TLR4, but not TLR2, in the lungs of WT septic mice. We also found that septic SRA−/− mice had lower bacterial burdens than WT septic mice. SRA deficiency had no effect on pulmonary neutrophil infiltration or splenocyte apoptosis during sepsis. We conclude that SRA plays a pivotal, and previously unknown, role in mediating the pathophysiology of sepsis/septic shock in a murine model of polymicrobial sepsis. Mechanistically, SRA interacts with TLR4 to enhance the development of the pro-inflammatory phenotype and mediate the morbidity and mortality of sepsis/septic shock.
机译：败血症是严重疾病中的常见并发症。尚不清楚该疾病的发生和传播所涉及的机制。清道夫受体A（SRA）是一种结合多种聚阴离子（例如氧化的LDL和内毒素）的膜受体。最近的研究表明，SRA在先天免疫应答中充当模式识别受体。本研究的目的是确定SRA在败血症中的作用。缺乏SRA（SRA -/-）和C57BL / 6JB / 6J（WT）的雄性小鼠进行盲肠结扎和穿刺（CLP），以诱发多菌血症。在肺中分析了NFκB活性，髓过氧化物酶活性以及SRA与toll样受体（TLR）4和TLR2的共缔合。分析脾脏的细胞凋亡。测定血清细胞因子和趋化因子。培养血液和腹膜液以消除需氧和厌氧细菌的负担。与野生型小鼠相比，SRA -/-化脓性小鼠的长期存活率显着提高（53.6％对3.6％，p <0.05）。与野生型败血病小鼠相比，SRA -/-败血症小鼠的肺中NFκB活性降低了45.5％（p <0.05）。与脓毒症WT小鼠相比，脓毒症SRA -/-小鼠的血清白介素（IL）-5，IL-6，IL-10和单核细胞趋化蛋白-1的水平显着降低（p <0.05 ）。我们发现在WT败血症小鼠的肺部，SRA与TLR4免疫沉淀，但与TLR2无关。我们还发现，败血性SRA -/-小鼠的细菌负担比野生型败血症的小鼠低。 SRA缺乏对败血症期间肺中性粒细胞浸润或脾细胞凋亡没有影响。我们得出的结论是，SRA在介导脓毒症/败血症性休克的小鼠微生物败血症模型中的病理生理过程中起着关键性的作用，以前是未知的。从机制上讲，SRA与TLR4相互作用以增强促炎表型的发展，并介导败血症/败血性休克的发病率和死亡率。

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