Neutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia

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

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.

MeSH terms

  • Animals
  • Blood Platelets / metabolism
  • Cell Aggregation
  • Cell Membrane / metabolism
  • Cyclophilin D
  • Cyclophilins / deficiency
  • Cyclophilins / metabolism
  • Gastrointestinal Tract / blood supply*
  • Gastrointestinal Tract / pathology*
  • Gastrointestinal Tract / physiopathology
  • Humans
  • Ischemia / complications*
  • Ischemia / physiopathology
  • Lung / blood supply
  • Lung / pathology*
  • Lung / physiopathology
  • Mice, Inbred C57BL
  • Neutrophils / pathology*
  • Phosphatidylserines / metabolism
  • Respiratory Distress Syndrome, Adult / pathology
  • Respiratory Distress Syndrome, Adult / physiopathology
  • Splanchnic Circulation
  • Thrombosis / etiology*
  • Thrombosis / pathology*

Substances

  • Cyclophilin D
  • PPIF protein, mouse
  • Phosphatidylserines
  • Cyclophilins