Neutrophil Extracellular Traps Induce Intestinal Damage and Thrombotic Tendency in Inflammatory Bowel Disease
Neutrophil Extracellular Traps Induce Intestinal Damage and Thrombotic Tendency in Inflammatory Bowel Disease
复制标题
DOI：
10.1093/ecco-jcc/jjz132
复制
发表时间：
2020-02-01
影响因子：
8
通讯作者：
Shi, Jialan
中科院分区：
文献类型：
--
作者：
Li, Tao;Wang, Chunxu;Shi, Jialan
背景和目的尽管炎症性结肠中存在中性粒细胞胞外陷阱（NETs）已被证实，但NETs，特别是循环NETs，在炎症性肠病（IBD）的进展和血栓形成倾向中的作用仍然难以确定。我们扩展了之前的研究，以证明NETs是IBD进展和血栓形成前状态的核心组成部分。方法对48例连续IBD患者进行分析。用3.5%葡聚糖硫酸钠（DSS）灌胃C57BL/6小鼠，连续6 d诱导急性结肠炎。采集IBD患者和小鼠结肠炎模型外周血中性粒细胞和血清。用流式细胞术和共聚焦显微镜对暴露的磷脂酰丝氨酸进行分析。使用凝血时间、纯化凝血复合物和纤维蛋白形成测定来评估促凝活性。结果：我们观察到活动性IBD患者血浆中和结肠组织中存在较高的NET水平。更重要的是，在DSS结肠炎小鼠中诱导NETs，抑制NET释放可减轻结肠炎以及结肠炎相关肿瘤的发生。在dss诱导的结肠炎中，通过给药DNase降解NET降低了细胞因子水平。此外，DNase治疗还显著减轻了dss诱导的结肠炎中观察到的加速血栓形成和血小板活化。NETs部分通过TLR2和TLR4触发PS阳性微粒释放和血小板和内皮细胞上的PS暴露，将其转化为促凝表型。结论活动性IBD患者net加重结肠组织损伤，并驱动血栓形成倾向。针对NET形成的策略可能为治疗IBD提供一种潜在的治疗方法。
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.