BACKGROUND AND AIMS Despite the presence of neutrophil extracellular traps [NETs] in inflamed colon having been confirmed, the role of NETs, especially the circulating NETs, in the progression and thrombotic tendency of inflammatory bowel disease [IBD] remains elusive. We extended our previous study to prove that NETs constitute a central component in the progression and prothrombotic state of IBD. METHODS In all 48 consecutive patients with IBD were studied. Acute colitis was induced by the treatment of C57BL/6 mice with 3.5% dextran sulphate sodium [DSS] in drinking water for 6 days. Peripheral blood neutrophils and sera were collected from IBD patients and murine colitis models. Exposed phosphatidylserine [PS] was analysed with flow cytometry and confocal microscopy. Procoagulant activity was evaluated using clotting time, purified coagulation complex, and fibrin formation assays. RESULTS We observed higher plasma NET levels and presence of NETs in colon tissue in patients with active IBD. More importantly, NETs were induced in mice with DSS colitis, and inhibition of NET release attenuated colitis as well as colitis-associated tumorigenesis. NET degradation through DNase administration decreased cytokine levels during DSS-induced colitis. In addition, DNase treatment also significantly attenuated the accelerated thrombus formation and platelet activation observed in DSS-induced colitis. NETs triggered PS-positive microparticle release and PS exposure on platelets and endothelial cells partially through TLR2 and TLR4, converting them to a procoagulant phenotype. CONCLUSIONS NETs exacerbate colon tissue damage and drive thrombotic tendency during active IBD. Strategies directed against NET formation may offer a potential therapeutic approach for the treatment of IBD.

中文翻译：

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中性粒细胞胞外诱集物在炎症性肠病中引起肠损伤和血栓形成倾向。

背景和目的尽管已经确认发炎的结肠中存在嗜中性粒细胞胞外诱捕器[NETs]，但是NETs，尤其是循环的NETs在炎症性肠病[IBD]的进展和血栓形成趋势中的作用仍然难以捉摸。我们扩展了先前的研究，以证明NETs是IBD病情发展和血栓形成前的重要组成部分。方法对所有48位连续的IBD患者进行研究。急性结肠炎是通过用饮用水中的3.5％葡聚糖硫酸钠[DSS]处理C57BL / 6小鼠6天而诱发的。从IBD患者和鼠结肠炎模型中收集外周血中性粒细胞和血清。用流式细胞仪和共聚焦显微镜分析暴露的磷脂酰丝氨酸[PS]。使用凝血时间评估促凝活性，纯化的凝血复合物和血纤蛋白形成测定。结果我们观察到活动性IBD患者血浆NET水平较高，结肠组织中存在NET。更重要的是，在患有DSS结肠炎的小鼠中诱发了NETs，抑制NET释放可减轻结肠炎以及与结肠炎相关的肿瘤发生。通过DNase施用引起的NET降解在DSS诱导的结肠炎期间降低了细胞因子水平。此外，DNase治疗还可显着减轻在DSS诱发的结肠炎中观察到的加速血栓形成和血小板活化。NETs通过TLR2和TLR4触发PS阳性微粒释放以及PS在血小板和内皮细胞上的暴露，从而将它们转化为促凝表型。结论在活跃的IBD期间，NETs加剧了结肠组织的损伤并驱动了血栓形成的趋势。