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

Lung Transplant Outcomes Group Investigators

Research output: Contribution to journalArticle

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

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Primary Graft Dysfunction
Lung Transplantation
Lung Injury
Cold Ischemia
Blood Platelets
Lung
Bronchoalveolar Lavage Fluid
Extracellular Traps
Transplants

Keywords

  • Acute lung injury
  • Immunity, innate
  • Inflammation

ASJC Scopus subject areas

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

Cite this

Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation. / Lung Transplant Outcomes Group Investigators.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 191, No. 4, 15.02.2015, p. 455-463.

Research output: Contribution to journalArticle

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title = "Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation",
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.",
keywords = "Acute lung injury, Immunity, innate, Inflammation",
author = "{Lung Transplant Outcomes Group Investigators} and Sayah, {David M.} and Be{\~n}at Mallavia and Fengchun Liu and Guadalupe Ortiz-Mu{\~n}oz and Axelle Caudrillier and Ariss DerHovanessian and Ross, {David J.} and Lynch, {Joseph P.} and Rajan Saggar and Abbas Ardehali and Ware, {Lorraine B.} and Christie, {Jason D.} and Belperio, {John A.} and Looney, {Mark R.} and Kawut, {Steven M.} and Edward Cantu and Joshua Diamond and Rupal Shah and Ejigayehu Demissie and Kotloff, {Robert M.} and Ayha, {Vivek N.} and James Lee and Denis Hadjiliadis and Melanie Ruschefski and Lederer, {David J.} and Arcasoy, {Selim M.} and Sonett, {Joshua R.} and Jessie Wilt and Frank D'Ovidio and Matthew Bacchetta and Hilary Robbins and Lori Shah and Nilani Ravichandran and Nadine Al-Naamani and Nisha Philip and Debbie Rybak and Matthew Lippell and Shefali Sanyal and Michael Koeckert and Amisha Desai and Megan Larkin and Brian Lim and Justin Shin and Robert Sorabella and Stephanie Logan and Ann Weinacker and Gundeep Dillon and Jacobs, {Susan Spencer} and Orens, {Jonathan B} and Shah, {Pali Dedhiya}",
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T1 - Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation

AU - Lung Transplant Outcomes Group Investigators

AU - Sayah, David M.

AU - Mallavia, Beñat

AU - Liu, Fengchun

AU - Ortiz-Muñoz, Guadalupe

AU - Caudrillier, Axelle

AU - DerHovanessian, Ariss

AU - Ross, David J.

AU - Lynch, Joseph P.

AU - Saggar, Rajan

AU - Ardehali, Abbas

AU - Ware, Lorraine B.

AU - Christie, Jason D.

AU - Belperio, John A.

AU - Looney, Mark R.

AU - Kawut, Steven M.

AU - Cantu, Edward

AU - Diamond, Joshua

AU - Shah, Rupal

AU - Demissie, Ejigayehu

AU - Kotloff, Robert M.

AU - Ayha, Vivek N.

AU - Lee, James

AU - Hadjiliadis, Denis

AU - Ruschefski, Melanie

AU - Lederer, David J.

AU - Arcasoy, Selim M.

AU - Sonett, Joshua R.

AU - Wilt, Jessie

AU - D'Ovidio, Frank

AU - Bacchetta, Matthew

AU - Robbins, Hilary

AU - Shah, Lori

AU - Ravichandran, Nilani

AU - Al-Naamani, Nadine

AU - Philip, Nisha

AU - Rybak, Debbie

AU - Lippell, Matthew

AU - Sanyal, Shefali

AU - Koeckert, Michael

AU - Desai, Amisha

AU - Larkin, Megan

AU - Lim, Brian

AU - Shin, Justin

AU - Sorabella, Robert

AU - Logan, Stephanie

AU - Weinacker, Ann

AU - Dillon, Gundeep

AU - Jacobs, Susan Spencer

AU - Orens, Jonathan B

AU - Shah, Pali Dedhiya

PY - 2015/2/15

Y1 - 2015/2/15

N2 - 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.

AB - 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.

KW - Acute lung injury

KW - Immunity, innate

KW - Inflammation

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U2 - 10.1164/rccm.201406-1086OC

DO - 10.1164/rccm.201406-1086OC

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VL - 191

SP - 455

EP - 463

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

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ER -