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Quiescent complement in nonhuman primates during E coli Shiga toxin-induced hemolytic uremic syndrome and thrombotic microangiopathy

发布于：2013年8月6日    文字：【大】【中】【小】

Blood. 2013 Aug 1;122(5):803-6. doi: 10.1182/blood-2013-03-490060. Epub 2013 Jun 3.

Quiescent complement in nonhuman primates during E coli Shiga toxin-induced hemolytic uremic syndrome and thrombotic microangiopathy.

Lee BC, Mayer CL, Leibowitz CS, Stearns-Kurosawa DJ, Kurosawa S.

Abstract

Enterohemorrhagic Escherichia coli (EHEC) produce ribosome-inactivating Shiga toxins (Stx1, Stx2) responsible for development of hemolytic uremic syndrome (HUS) and acute kidney injury (AKI). Some patients show complement activation during EHEC infection, raising the possibility of therapeutic targeting of complement for relief. Our juvenile nonhuman primate (Papio baboons) models of endotoxin-free Stx challenge exhibit full spectrum HUS, including thrombocytopenia, hemolytic anemia, and AKI with glomerular thrombotic microangiopathy. There were no significant increases in soluble terminal complement complex (C5b-9) levels after challenge with lethal Stx1 (n = 6) or Stx2 (n = 5) in plasma samples from T0 to euthanasia at 49.5 to 128 hours post-challenge. d-dimer and cell injury markers (HMGB1, histones) confirmed coagulopathy and cell injury. Thus, complement activation is not required for the development of thrombotic microangiopathy and HUS induced by EHEC Shiga toxins in these preclinical models, and benefits or risks of complement inhibition should be studied further for this infection.

产志贺毒素的大肠埃希菌引起溶血尿毒综合征（D+HUS）的机制为志贺毒素灭活内皮细胞核糖体、蛋白合成障碍，最终导致细胞凋亡或坏死；内皮细胞损伤后激活凝血，造成HUS的病理生理改变。内皮细胞损伤、凝血激活及炎症细胞活化后会继发补体活化，之前报道在D+HUS病情加重中发挥作用；2011年德国爆发的D+HUS、在重症患者使用抗C5单抗取得了明显疗效，也支持补体活化在D+HUS发病中的作用。

但是，此报道给Papio狒狒注射志贺毒素后成功建立HUS动物模型，但发现其血浆sC5b-9无升高。提出补体活化不是发生血栓性微血管病的必要条件；这与之前的发现一致；但结合此报道的结果，内皮细胞损伤后是否继发补体活化、及其在D+HUS病情加重的作用与之前报道出现不一致。

http://www.ncbi.nlm.nih.gov/pubmed/23733336