RT Journal Article
SR Electronic
T1 Neutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaam5861
DO 10.1126/scitranslmed.aam5861
VO 9
IS 409
A1 Yuan, Yuping
A1 Alwis, Imala
A1 Wu, Mike C. L.
A1 Kaplan, Zane
A1 Ashworth, Katrina
A1 Bark, David
A1 Pham, Alan
A1 Mcfadyen, James
A1 Schoenwaelder, Simone M.
A1 Josefsson, Emma C.
A1 Kile, Benjamin T.
A1 Jackson, Shaun P.
YR 2017
UL http://stm.sciencemag.org/content/9/409/eaam5861.abstract
AB Ischemia in critically ill patients can result in thrombosis of unrelated organs, which is partially due to neutrophil recruitment. Yuan et al. combined intravital microscopy of thrombosis after gut ischemia-reperfusion injury with samples from acute respiratory distress syndrome patients. They observed that rolling neutrophils grab and rip fragments from phosphatidylserine-expressing dying platelets, which leads to macroaggregates. These macroaggregates, in turn, induce thrombosis and were not able to be targeted by conventional therapies such as aspirin. Conversely, targeting the necrotic factor cyclophilin D did have beneficial effects. These studies reveal new thrombotic biology and suggest the development of alternatively targeted therapies to prevent distant organ injury.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.