Australian Centre for Blood Diseases, Alfred Medical and Research Education Precinct, Monash University, Melbourne, Victoria 3004, Australia.
Heart Research Institute, Newtown, New South Wales 2042, Australia.
Sci Transl Med. 2017 Sep 27;9(409). doi: 10.1126/scitranslmed.aam5861.
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.
肠道缺血在危重病患者中很常见，会促进远隔器官的血栓形成和炎症反应。将肠道血流动力学变化与远隔器官血栓形成联系起来的机制仍不清楚。我们证明，小鼠的肠道缺血会引发一种独特的肺部血栓性疾病，这种疾病是由中性粒细胞聚集体引发的。这些中性粒细胞聚集导致广泛的肺动脉、静脉和微血管闭塞。急性呼吸窘迫综合征患者也会出现类似的富含中性粒细胞的肺部血栓反应。在肠道缺血再灌注损伤期间的活体显微镜检查显示，滚动的中性粒细胞从多个器官中残留的死亡血小板中提取出大量的膜片段。这些血小板片段将相邻的中性粒细胞桥接起来，促进了巨聚集。血小板特异性敲除细胞坏死的线粒体调节剂环孢素 D 可防止中性粒细胞巨聚集和肺血栓形成。我们的研究表明，死亡血小板和中性粒细胞聚集体会引发一种独特的肺部血栓性疾病。针对血小板死亡途径的治疗可能会减少危重病患者的肺部血栓形成。
