Research Publications


Neutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia

Yuan, Y; Alwis, I; Wu, MCL; Kaplan, Z; Ashworth, K; Bark, D, Jr; Pham, A; McFadyen, J; Schoenwaelder, SM; Josefsson, EC; Kile, BT; Jackson, SP
Science Translational Medicine
Journal Article
pii: eaam5861
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.
Cancer and Haematology
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Creation Date 2017-10-16 02:00:21 Last Modified 2018-06-27 09:42:46