Recombinant human DNase-I improves acute respiratory distress syndrome via neutrophil extracellular trap degradation.
Recombinant human DNase-I improves acute respiratory distress syndrome via neutrophil extracellular trap degradation.
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DOI：
10.1016/j.jtha.2023.04.044
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发表时间：
2023-09
影响因子：
10.4
通讯作者：
Dhandapani, Krishnan M.
中科院分区：
文献类型：
--
作者：
Jarrahi, Abbas;Khodadadi, Hesam;Moore, Nicholas S.;Lu, Yujiao;Awad, Mohamed E.;Salles, Evila L.;Vaibhav, Kumar;Baban, Babak;Dhandapani, Krishnan M.
呼吸衰竭是COVID-19患者死亡的主要原因，而凝血功能障碍与过度炎症和多器官衰竭有关。神经细胞外陷阱（NET）可能会加剧炎症，并为血栓形成提供支架。本研究的目的是确定重组人DNA酶-I（rhDNase）（一种安全的食品和药物管理局批准的药物）降解NET是否能减少过度炎症，逆转异常凝血，并改善实验性急性呼吸窘迫综合征（ARDS）后的肺灌注。鼻内聚（I：C），一种合成的双链RNA，连续3天给予成年小鼠以模拟病毒感染，这些受试者被随机分配到治疗组，接受静脉注射安慰剂或rhDNase。在小鼠和供体人血液中评估rhDNase对免疫活化、血小板聚集和凝血的影响。实验性ARDS后支气管肺泡灌洗液和缺氧肺组织内均可见NETs。rhDNase的给药减轻了poly（I：C）诱导的细支气管周围、血管周围和间质性炎症。与此同时，rhDNase降解NET，衰减血小板-NET聚集体，减少血小板活化，并使凝血时间正常化以改善局部灌注，如在小鼠中使用大体形态学、组织学和显微计算机断层扫描成像所观察到的。类似地，rhDNase减少了人类血液中的NET并减弱了血小板活化。NET通过为实验性ARDS后聚集的血小板提供支架而加剧炎症并促进异常凝血。静脉注射rhDNase可降解NETs并减轻ARDS中的凝血障碍，为改善ARDS后肺结构和功能提供了一种有前途的转化方法。
Respiratory failure is the primary cause of death in patients with COVID-19, whereas coagulopathy is associated with excessive inflammation and multiorgan failure. Neutrophil extracellular traps (NETs) may exacerbate inflammation and provide a scaffold for thrombus formation. The goal of this study was to determine whether degradation of NETs by recombinant human DNase-I (rhDNase), a safe, Food and Drug Administration–approved drug, reduces excessive inflammation, reverses aberrant coagulation, and improves pulmonary perfusion after experimental acute respiratory distress syndrome (ARDS). Intranasal poly(I:C), a synthetic double-stranded RNA, was administered to adult mice for 3 consecutive days to simulate a viral infection, and these subjects were randomized to treatment arms, which received either an intravenous placebo or rhDNase. The effects of rhDNase on immune activation, platelet aggregation, and coagulation were assessed in mice and donor human blood. NETs were observed in bronchoalveolar lavage fluid and within regions of hypoxic lung tissue after experimental ARDS. The administration of rhDNase mitigated peribronchiolar, perivascular, and interstitial inflammation induced by poly(I:C). In parallel, rhDNase degraded NETs, attenuated platelet-NET aggregates, reduced platelet activation, and normalized the clotting time to improve regional perfusion, as observed using gross morphology, histology, and microcomputed tomographic imaging in mice. Similarly, rhDNase reduced NETs and attenuated platelet activation in human blood. NETs exacerbate inflammation and promote aberrant coagulation by providing a scaffold for aggregated platelets after experimental ARDS. Intravenous administration of rhDNase degrades NETs and attenuates coagulopathy in ARDS, providing a promising translational approach to improve pulmonary structure and function after ARDS.
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影响因子：
28.2
作者：
Liu, Yuwei;Du, Xuebei;Zhao, Yan
通讯作者：
Zhao, Yan
DOI：
10.1001/archotol.131.12.1097
发表时间：
2005-12-01
影响因子：
--
作者：
Cimmino, M;Nardone, M;Raia, V
通讯作者：
Raia, V
影响因子：
81.5
作者：
Matthay, Michael A.;Zemans, Rachel L.;Calfee, Carolyn S.
通讯作者：
Calfee, Carolyn S.
影响因子：
20.3
作者：
Martinod, Kimberly;Fuchs, Tobias A.;Wagner, Denisa D.
通讯作者：
Wagner, Denisa D.
DOI：
10.1016/j.lpm.2011.05.027
发表时间：
2011-12
期刊：
Presse medicale (Paris, France : 1983)
影响因子：
--
作者：
Luyt CÉ;Combes A;Trouillet JL;Nieszkowska A;Chastre J
通讯作者：
Chastre J