Inhibition of peptidylarginine deiminase alleviates LPS-induced pulmonary dysfunction and improves survival in a mouse model of lethal endotoxemia.
Inhibition of peptidylarginine deiminase alleviates LPS-induced pulmonary dysfunction and improves survival in a mouse model of lethal endotoxemia.
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DOI：
10.1016/j.ejphar.2018.07.005
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发表时间：
2018-08-15
影响因子：
5
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Liang Y;Pan B;Alam HB;Deng Q;Wang Y;Chen E;Liu B;Tian Y;Williams AM;Duan X;Wang Y;Zhang J;Li Y
中性粒细胞胞外陷阱(NETs)引起的免疫细胞死亡，称为NETsis，是内毒素血症和器官损害的重要致病因素。尽管感染引起网织红细胞增多症的机制以及如何导致器官功能障碍仍不清楚，但在组蛋白H3(CitH3)被肽基精氨酸脱亚胺酶(PAD)瓜氨酸化后，网状结构经常被发现。我们推测，脂多糖(LPS)诱导的PAD激活和随后的CitH3介导的Net形成增加了内皮通透性和肺功能障碍，因此，抑制PAD可以减轻致死性内毒素血症的损害并提高存活率。在这里，我们显示了PAD2/PAD4抑制剂YW3-56的治疗显著降低了PAD的激活，阻断了内毒素诱导的肺血管渗漏，减轻了急性肺损伤，并提高了致死性内毒素血症小鼠的存活率。小鼠腹腔注射脂多糖(35 mg/kg)30min后，血流中可见CitH3。此外，培养的中性粒细胞暴露于脂多糖可诱导CitH3的产生，而这些中性粒细胞经脂多糖处理后产生的Net可增加内皮细胞的通透性。然而，YW3-56暴露减少了脂多糖暴露后CitH3的产生和中性粒细胞的净形成。此外，YW3-56还能降低内毒素血症小鼠肺循环中CitH3的水平，并取消中性粒细胞的激活和网状形成。这些数据提示了Pad-Net-CitH3在肺血管功能障碍和致死性内毒素血症的发病机制中发挥关键作用的新机制。
Immune cell death caused by neutrophil extracellular traps (NETs), referred to as NETosis, can contribute to the pathogenesis of endotoxemia and organ damage. Although the mechanisms by which infection induces NETosis and how that leads to organ dysfunction remain largely unknown, NET formation is often found following citrullination of histone H3 (CitH3) by peptidylarginine deiminase (PAD). We hypothesized that lipopolysaccharide (LPS)-induced activation of PAD and subsequent CitH3-mediated NET formation increase endothelial permeability and pulmonary dysfunction and, therefore, that inhibition of PAD could mitigate damage and improve survival in lethal endotoxemia. Here, we showed that treatment with YW3-56, a PAD2/PAD4 inhibitor, significantly diminished PAD activation, blocked LPS-induced pulmonary vascular leakage, alleviated acute lung injury, and improved survival in a mouse model of lethal LPS-induced endotoxemia. We found CitH3 in the bloodstream 30 min after intraperitoneal injection of LPS (35 mg/kg) into mice. Additionally, CitH3 production was induced in cultured neutrophils exposed to LPS, and NETs derived from these LPS-treated neutrophils increased the permeability of endothelial cells. However, YW3-56 exposure reduced CitH3 production and NET formation by neutrophils following LPS exposure. Moreover, treatment with YW3-56 decreased the levels of circulating CitH3 and abolished neutrophil activation and NET formation in the lungs of mice with endotoxemia. These data suggest a novel mechanism by which PAD-NET-CitH3 can play a pivotal role in pulmonary vascular dysfunction and the pathogenesis of lethal endotoxemia.
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影响因子：
3.5
作者：
Ruiz S;Vardon-Bounes F;Merlet-Dupuy V;Conil JM;Buléon M;Fourcade O;Tack I;Minville V
通讯作者：
Minville V
细胞外组蛋白是败血症死亡的主要介体。
影响因子：
82.9
作者：
通讯作者：
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影响因子：
3.8
作者：
Li, Yongqing;Liu, Zhengcai;Liu, Baoling;Zhao, Ting;Chong, Wei;Wang, Yanming;Alam, Hasan B.
通讯作者：
Alam, Hasan B.
DOI：
10.1083/jcb.200806072
发表时间：
2009-01-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Wang Y;Li M;Stadler S;Correll S;Li P;Wang D;Hayama R;Leonelli L;Han H;Grigoryev SA;Allis CD;Coonrod SA
通讯作者：
Coonrod SA
影响因子：
82.9
作者：
通讯作者：
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