Gut ischemia is common in critically ill patients, promoting thrombosis and inflammation in distant organs. The mechanisms linking hemodynamic changes in the gut to remote organ thrombosis remain ill-defined. We demonstrate that gut ischemia in the mouse induces a distinct pulmonary thrombotic disorder triggered by neutrophil macroaggregates. These neutrophil aggregates lead to widespread occlusion of pulmonary arteries, veins, and the microvasculature. A similar pulmonary neutrophil-rich thrombotic response occurred in humans with the acute respiratory distress syndrome. Intravital microscopy during gut ischemia-reperfusion injury revealed that rolling neutrophils extract large membrane fragments from remnant dying platelets in multiple organs. These platelet fragments bridge adjacent neutrophils to facilitate macroaggregation. Platelet-specific deletion of cyclophilin D, a mitochondrial regulator of cell necrosis, prevented neutrophil macroaggregation and pulmonary thrombosis. Our studies demonstrate the existence of a distinct pulmonary thrombotic disorder triggered by dying platelets and neutrophil macroaggregates. Therapeutic targeting of platelet death pathways may reduce pulmonary thrombosis in critically ill patients.

中文翻译：

---

中性粒细胞大聚集体促进肠道缺血后广泛的肺血栓形成。

肠道缺血在重症患者中很常见，可促进远处器官的血栓形成和炎症。肠道血流动力学变化与远端器官血栓形成相关的机制仍然不清楚。我们证明在小鼠中的肠缺血诱导由嗜中性粒细胞大聚集物触发的独特的肺血栓性疾病。这些中性粒细胞聚集体导致广泛阻塞肺动脉，静脉和微脉管系统。患有急性呼吸窘迫综合征的人发生了类似的富含肺中性粒细胞的血栓反应。肠道缺血-再灌注损伤期间的活体显微镜检查显示，滚动中性粒细胞从多个器官中残留的垂死血小板中提取出大的膜碎片。这些血小板片段桥接相邻的嗜中性粒细胞，以促进宏观聚集。血小板亲和素D（一种细胞坏死的线粒体调节剂）的血小板特异性缺失阻止了中性粒细胞的大量聚集和肺血栓形成。我们的研究表明存在由血小板和嗜中性粒细胞大分子垂死引发的独特的肺血栓形成疾病。靶向治疗血小板死亡途径可以减轻危重患者的肺血栓形成。