• David M Sayah, Beñat Mallavia, Fengchun Liu, Guadalupe Ortiz-Muñoz, Axelle Caudrillier, Ariss DerHovanessian, David J Ross, Joseph P Lynch, Rajan Saggar, Abbas Ardehali, Lung Transplant Outcomes Group Investigators, Lorraine B Ware, Jason D Christie, John A Belperio, and Mark R Looney.
• 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.
• Am. J. Respir. Crit. Care Med.. 2015 Feb 15;191(4):455-63.

RationalePrimary 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.ObjectivesTo study NETs in experimental models of PGD and in lung transplant patients.MethodsTwo 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.Measurements And Main ResultsNETs 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.ConclusionsNETs 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.

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