Neutrophil Extracellular Traps Are Pathogenic in Primary Graft Dysfunction after Lung Transplantation
Neutrophil Extracellular Traps Are Pathogenic in Primary Graft Dysfunction after Lung Transplantation
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DOI：
10.1164/rccm.201406-1086oc
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发表时间：
2015-02-15
影响因子：
24.7
通讯作者：
Looney, Mark R.
中科院分区：
文献类型：
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作者：
Sayah, David M.;Mallavia, Benat;Looney, Mark R.
原理：原发性移植物功能障碍（PGD）导致肺移植后早期死亡，并可能导致晚期移植物衰竭。没有有效的治疗方法。PGD的发病机制尚不清楚，尽管中性粒细胞和活化的血小板都有牵连。我们假设，中性粒细胞胞外陷阱（NETs）有助于肺损伤PGD中的血小板依赖martens. Objective. To研究NETs在实验模型PGD和肺移植patients.Methods：两个实验鼠PGD模型进行了研究：肺门钳和原位肺移植后长时间冷缺血（OLT-PCI）。通过免疫荧光显微镜和ELISA评估NET。血小板活化被阿司匹林抑制，NET被DNaseI破坏。NETs也测定了支气管肺泡灌洗液和血浆中的肺移植患者与PGD. Measures和主要结果：无论是肺门钳或OLT-PCI后增加与手术对照组相比。OLT-PCI中血小板的活化和肺内积聚增加，血小板抑制减少了NETs和肺损伤，并改善了氧合。通过支气管内给予DNaseI破坏NET也减少了肺损伤并改善了氧合。在人肺移植受者的支气管肺泡灌洗液中，NETs在PGD患者中更丰富。结论：NETs在实验和临床PGD中均在肺中积聚。在实验性PGD中，NET的形成是血小板依赖性的，并且用DNaseI破坏NET可以减少肺损伤。这些数据是第一次描述的致病作用NET在实体器官移植，并表明，NET是一个有前途的治疗靶点PGD。
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 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.