H(2) Inhibits the Formation of Neutrophil Extracellular Traps.
H(2) Inhibits the Formation of Neutrophil Extracellular Traps.
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DOI：
10.1016/j.jacbts.2021.11.005
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Sano M
中科院分区：
文献类型：
--
作者：
Shirakawa K;Kobayashi E;Ichihara G;Kitakata H;Katsumata Y;Sugai K;Hakamata Y;Sano M
NET已经被认为是治疗靶点，以解决败血症、急性呼吸道疾病综合征、COVID-19和CVD等病症中的炎症和血栓性组织损伤。H2已被临床和实验证明可以改善炎症;然而，潜在的分子机制仍然难以捉摸。与对照中性粒细胞相比，暴露于H2的PMA刺激的人中性粒细胞表现出组蛋白的瓜氨酸减少和NET组分的释放;从机制上讲，H2介导的氧化爆发期间产生的HOCl中和抑制DNA损伤。吸入H2可抑制LPS诱导的脓毒症小鼠和老龄小型猪血液和BAL中NET成分的形成和释放。H2疗法可能是一种新的治疗策略，用于涉及与中性粒细胞过度活化相关的NETs的炎性疾病。神经细胞外陷阱（NETs）有助于炎症发病机制在许多情况下，包括感染性和心血管疾病，并已引起人们的注意，作为潜在的治疗靶点。H2作为一种抗氧化剂，已被临床和实验证明可以改善炎症。本研究旨在研究H2是否能抑制NET形成和过度的中性粒细胞活化。从健康志愿者的血液中分离的中性粒细胞用佛波醇-12-肉豆蔻酸酯-13-乙酸酯（PMA）或钙离子载体A23187在H2暴露或对照培养基中刺激。与对照中性粒细胞相比，PMA-或A23187-刺激的人中性粒细胞暴露于H2表现出减少中性粒细胞聚集，组蛋白的瓜氨酸化，染色质复合物的膜破坏，和NET组件的释放。CXCR 4高中性粒细胞高度倾向于NET，H2抑制H2 AX中Ser-139磷酸化，这是DNA损伤的标志物，从而抑制CXCR 4表达的诱导。H2抑制髓过氧化物酶氯化活性和活性氧的产生，以相同的程度作为N-乙酰半胱氨酸和抗坏血酸，同时显示出更有效的能力，抑制NET的形成比这些抗氧化剂在PMA刺激的中性粒细胞。尽管A23187以活性氧不依赖的方式形成NET，但H2可能通过直接抑制肽基精氨酸脱亚胺酶4介导的组蛋白瓜氨酸酶来抑制A23187诱导的NET形成。在脂多糖诱导的脓毒症动物模型（小鼠和老年小型猪）中，吸入H2抑制血液和支气管肺泡灌洗液中NET组分的形成和释放。因此，H2疗法可以是与过度中性粒细胞活化相关的NET的新的治疗策略。
NETs have been implicated as therapeutic targets to address inflammation and thrombotic tissue damage in conditions such as sepsis, acute respiratory disease syndrome, COVID-19, and CVDs. H2 has been clinically and experimentally proven to ameliorate inflammation; however, the underlying molecular mechanisms remain elusive. Compared with control neutrophils, PMA-stimulated human neutrophils exposed to H2 exhibited reduced citrullination of histones and release of NET components; mechanistically, H2-mediated neutralization of HOCl produced during oxidative bursts suppresses DNA damage. Inhalation of H2 inhibited the formation and release of NET components in the blood and BAL of the LPS-induced sepsis in mice and aged mini pigs. H2 therapy is potentially a new therapeutic strategy for inflammatory diseases involving NETs associated with excessive neutrophil activation. Neutrophil extracellular traps (NETs) contribute to inflammatory pathogenesis in numerous conditions, including infectious and cardiovascular diseases, and have attracted attention as potential therapeutic targets. H2 acts as an antioxidant and has been clinically and experimentally proven to ameliorate inflammation. This study was performed to investigate whether H2 could inhibit NET formation and excessive neutrophil activation. Neutrophils isolated from the blood of healthy volunteers were stimulated with phorbol-12-myristate-13-acetate (PMA) or the calcium ionophore A23187 in H2-exposed or control media. Compared with control neutrophils, PMA- or A23187-stimulated human neutrophils exposed to H2 exhibited reduced neutrophil aggregation, citrullination of histones, membrane disruption by chromatin complexes, and release of NET components. CXCR4high neutrophils are highly prone to NETs, and H2 suppressed Ser-139 phosphorylation in H2AX, a marker of DNA damage, thereby suppressing the induction of CXCR4 expression. H2 suppressed both myeloperoxidase chlorination activity and production of reactive oxygen species to the same degree as N-acetylcysteine and ascorbic acid, while showing a more potent ability to inhibit NET formation than these antioxidants do in PMA-stimulated neutrophils. Although A23187 formed NETs in a reactive oxygen species–independent manner, H2 inhibited A23187-induced NET formation, probably via direct inhibition of peptidyl arginine deiminase 4-mediated histone citrullination. Inhalation of H2 inhibited the formation and release of NET components in the blood and bronchoalveolar lavage fluid in animal models of lipopolysaccharide-induced sepsis (mice and aged mini pigs). Thus, H2 therapy can be a novel therapeutic strategy for NETs associated with excessive neutrophil activation.
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影响因子：
7.3
作者：
Konig MF;Andrade F
通讯作者：
Andrade F
影响因子：
15.9
作者：
Eash, Kyle J.;Greenbaum, Adam M.;Link, Daniel C.
通讯作者：
Link, Daniel C.
影响因子：
32.4
作者：
Adrover, Jose M.;del Fresno, Carlos;Hidalgo, Andres
通讯作者：
Hidalgo, Andres
DOI：
10.1016/j.bbrc.2008.05.165
发表时间：
2008-08-15
影响因子：
3.1
作者：
Hayashida, Kentaro;Sano, Motoaki;Fukuda, Keiichi
通讯作者：
Fukuda, Keiichi
影响因子：
158.5
作者：
Ackermann, Maximilian;Verleden, Stijn E.;Jonigk, Danny
通讯作者：
Jonigk, Danny