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Sci Transl Med. 2017 Sep 27;9(409). pii: eaam5861. doi: 10.1126/scitranslmed.aam5861.

Neutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia.

Author information

1
Australian Centre for Blood Diseases, Alfred Medical and Research Education Precinct, Monash University, Melbourne, Victoria 3004, Australia.
2
Heart Research Institute, Newtown, New South Wales 2042, Australia.
3
Charles Perkins Centre, University of Sydney, New South Wales 2006, Australia.
4
Department of Anatomical Pathology, Alfred Hospital, Prahran, Victoria 3181, Australia.
5
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
6
Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
7
Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3168, Australia.
8
Australian Centre for Blood Diseases, Alfred Medical and Research Education Precinct, Monash University, Melbourne, Victoria 3004, Australia. shaun.jackson@sydney.edu.au.
9
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.

Abstract

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.

PMID:
28954929
DOI:
10.1126/scitranslmed.aam5861
[Indexed for MEDLINE]

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