Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation

David M. Sayah*, Beñat Mallavia, Fengchun Liu, Guadalupe Ortiz-Muñoz, Axelle Caudrillier, Ariss DerHovanessian, David J. Ross, Joseph P. Lynch, Rajan Saggar, Abbas Ardehali, Lorraine B. Ware, Jason D. Christie, John A. Belperio, Mark R. Looney, Steven M. Kawut, Edward Cantu, Joshua Diamond, Rupal Shah, Ejigayehu Demissie, Robert M. KotloffVivek N. Ayha, James Lee, Denis Hadjiliadis, Melanie Ruschefski, David J. Lederer, Selim M. Arcasoy, Joshua R. Sonett, Jessie Wilt, Frank D'Ovidio, Matthew Bacchetta, Hilary Robbins, Lori Shah, Nilani Ravichandran, Nadine Al-Naamani, Nisha Philip, Debbie Rybak, Matthew Lippell, Shefali Sanyal, Michael Koeckert, Amisha Desai, Megan Larkin, Brian Lim, Justin Shin, Robert Sorabella, Stephanie Logan, Ann Weinacker, Gundeep Dillon, Susan Spencer Jacobs, Val Scott, Sangeeta Bhorade, Lung Transplant Outcomes Group Investigators

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Rationale: 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. Objectives: 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. Measurements and Main 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 plateletdependent, 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.

Original languageEnglish (US)
Pages (from-to)455-463
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume191
Issue number4
DOIs
StatePublished - Feb 15 2015

Keywords

  • Acute lung injury
  • Immunity, innate
  • Inflammation

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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