title: Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation.
abstract: BACKGROUND
  Primary graft dysfunction (PGD) causes early mortality after lung transplantation and may contribute to late graft failure. No effective treatments exist. The pathogenesis of PGD is unclear, although both neutrophils and activated platelets have been implicated. We hypothesized that neutrophil extracellular traps (NETs) contribute to lung injury in PGD in a platelet-dependent manner.
  
  
  OBJECTIVE
  To study NETs in experimental models of PGD and in lung transplant patients.
  
  
  METHODS
  Two experimental murine PGD models were studied: hilar clamp and orthotopic lung transplantation after prolonged cold ischemia (OLT-PCI). NETs were assessed by immunofluorescence microscopy and ELISA. Platelet activation was inhibited with aspirin, and NETs were disrupted with DNaseI. NETs were also measured in bronchoalveolar lavage fluid and plasma from lung transplant patients with and without PGD.
  
  
  RESULTS
  NETs were increased after either hilar clamp or OLT-PCI compared with surgical control subjects. Activation and intrapulmonary accumulation of platelets were increased in OLT-PCI, and platelet inhibition reduced NETs and lung injury, and improved oxygenation. Disruption of NETs by intrabronchial administration of DNaseI also reduced lung injury and improved oxygenation. In bronchoalveolar lavage fluid from human lung transplant recipients, NETs were more abundant in patients with PGD.
  
  
  CONCLUSIONS
  NETs accumulate in the lung in both experimental and clinical PGD. In experimental PGD, NET formation is platelet-dependent, and disruption of NETs with DNaseI reduces lung injury. These data are the first description of a pathogenic role for NETs in solid organ transplantation and suggest that NETs are a promising therapeutic target in PGD.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.
authors.forename: David M
authors.initials: DM
authors.lastname: Sayah
authors.forename: Beñat
authors.initials: B
authors.lastname: Mallavia
authors.forename: Fengchun
authors.initials: F
authors.lastname: Liu
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Ortiz-Muñoz
authors.forename: Axelle
authors.initials: A
authors.lastname: Caudrillier
authors.forename: Ariss
authors.initials: A
authors.lastname: DerHovanessian
authors.forename: David J
authors.initials: DJ
authors.lastname: Ross
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lynch
authors.forename: Rajan
authors.initials: R
authors.lastname: Saggar
authors.forename: Abbas
authors.initials: A
authors.lastname: Ardehali
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.forename: John A
authors.initials: JA
authors.lastname: Belperio
authors.forename: Mark R
authors.initials: MR
authors.lastname: Looney
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D065206:Extracellular Traps / Q000378:metabolism*; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000378:metabolism*; D015539:Platelet Activation; D055031:Primary Graft Dysfunction / Q000097:blood / Q000276:immunology* / Q000473:pathology
chemical_list: D015415:Biomarkers
keywords: acute lung injury; immunity; inflammation; innate