Neutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia

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dc.contributor.authorYuan, Y.
dc.contributor.authorAlwis, I.
dc.contributor.authorWu, M.C.L.
dc.contributor.authorKaplan, Z.
dc.contributor.authorAshworth, K.
dc.contributor.authorBark, D.
dc.contributor.authorPham, A.
dc.contributor.authorMcFadyen, J.
dc.contributor.authorSchoenwaelder, S.M.
dc.contributor.authorJosefsson, E.C.
dc.contributor.authorKile, B.T.
dc.contributor.authorJackson, S.P.
dc.date.issued2017
dc.description.abstractGut 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.
dc.description.statementofresponsibilityYuping Yuan, Imala Alwis, Mike C. L. Wu, Zane Kaplan, Katrina Ashworth, David Bark Jr, Alan Pham, James Mcfadyen, Simone M. Schoenwaelder, Emma C. Josefsson, Benjamin T. Kile and Shaun P. Jackson
dc.identifier.citationScience Translational Medicine, 2017; 9(409):eaam5861-1-eaam5861-14
dc.identifier.doi10.1126/scitranslmed.aam5861
dc.identifier.issn1946-6234
dc.identifier.issn1946-6242
dc.identifier.orcidKile, B.T. [0000-0002-8836-8947]
dc.identifier.urihttp://hdl.handle.net/2440/121751
dc.language.isoen
dc.publisherAmerican Association for the Advancement of Science
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1127278
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1079400
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1023029
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1016647
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/9000220
dc.rights© 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
dc.source.urihttps://doi.org/10.1126/scitranslmed.aam5861
dc.subjectRespiratory Distress Syndrome, Adult
dc.titleNeutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia
dc.typeJournal article
pubs.publication-statusPublished

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