Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury
Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury
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DOI：
10.1172/jci.insight.98178
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发表时间：
2018-02-08
期刊：
影响因子：
8
通讯作者：
Looney, Mark R.
中科院分区：
文献类型：
--
作者：
Lefrancais, Emma;Mallavia, Benat;Looney, Mark R.
中性粒细胞在病原体诱导的急性肺损伤中占主导地位的早期免疫反应，但利用其反应的努力并未导致治疗进展。已经提出神经元胞外陷阱（NETs）作为负责病原体清除的先天防御机制，但是存在NETs可能诱导对宿主组织的附带损伤的担忧。在这里，我们在严重细菌性肺炎/急性肺损伤的小鼠模型和患有肺炎或脓毒症引起的急性呼吸窘迫综合征（ARDS）的人类受试者中检测到大量NET。减少NET可减少DNase I治疗或部分蛋白精氨酸脱亚胺酶4缺乏（PAD 4（+/-））后的肺损伤并改善存活率。完全PAD 4缺陷（PAD 4（-/-））减少NET和肺损伤，但被增加的细菌负荷和炎症抵消。重要的是，我们发现脂氧素途径可能是NET形成的有效调节剂，并且脂氧素受体（Fpr 2（-/-））缺陷的小鼠产生过量的NET，导致肺损伤和死亡率增加。最后，我们在人类中观察到，血浆NET增加与ARDS严重程度和死亡率相关，而血浆DNA酶I水平降低与脓毒症诱导的ARDS的发展相关。我们的结论是，一个关键的平衡NET是必要的，以防止肺损伤，并保持微生物控制，这具有重要的治疗意义。
Neutrophils dominate the early immune response in pathogen-induced acute lung injury, but efforts to harness their responses have not led to therapeutic advancements. Neutrophil extracellular traps (NETs) have been proposed as an innate defense mechanism responsible for pathogen clearance, but there are concerns that NETs may induce collateral damage to host tissues. Here, we detected NETs in abundance in mouse models of severe bacterial pneumonia/acute lung injury and in human subjects with acute respiratory distress syndrome (ARDS) from pneumonia or sepsis. Decreasing NETs reduced lung injury and improved survival after DNase I treatment or with partial protein arginine deiminase 4 deficiency (PAD4(+/-)). Complete PAD4 deficiency (PAD4(-/-)) reduced NETs and lung injury but was counterbalanced by increased bacterial load and inflammation. Importantly, we discovered that the lipoxin pathway could be a potent modulator of NET formation, and that mice deficient in the lipoxin receptor (Fpr2(-/-)) produced excess NETs leading to increased lung injury and mortality. Lastly, we observed in humans that increased plasma NETs were associated with ARDS severity and mortality, and lower plasma DNase I levels were associated with the development of sepsis-induced ARDS. We conclude that a critical balance of NETs is necessary to prevent lung injury and to maintain microbial control, which has important therapeutic implications.