Endotoxemia induced by lipopolysaccharide (LPS) is an extremely severe syndrome identified by global activation of inflammatory responses. Neutrophil extracellular traps (NETs) play an important role in the development of endotoxemia. Histone hypercitrullination catalyzed by peptidylarginine deiminases (PADs) is a key step of NET formation. We have previously demonstrated that simultaneous inhibition of PAD2 and PAD4 with pan-PAD inhibitors can decrease NETosis and improve survival in a mouse model of LPS-induced endotoxic shock. However, the effects of PAD2 specific inhibition during NETosis and endotoxic shock are poorly understood. Therefore, in the present study, we aimed to investigate the effect of the specific PAD2 or PAD4 inhibitor on LPS-induced endotoxic shock in mice. We found that PAD2 inhibition but not PAD4 inhibition improves survival. Also, the levels of proinflammatory cytokines and NETosis were significantly reduced by PAD2 inhibitor. To our knowledge, this study demonstrates for the first time that PAD2 inhibition can reduce NETosis, decrease inflammatory cytokine production, and protect against endotoxin-induced lethality. Our findings provided a novel therapeutic strategy for the treatment of endotoxic shock.

中文翻译：

---

抑制 PAD2 可提高致死性 LPS 诱导的内毒素休克小鼠模型的存活率。

脂多糖 (LPS) 诱导的内毒素血症是一种极其严重的综合征，由炎症反应的全局激活所确定。中性粒细胞胞外陷阱（NETs）在内毒素血症的发展中起重要作用。肽精氨酸脱亚胺酶 (PADs) 催化的组蛋白高瓜氨酸化是 NET 形成的关键步骤。我们之前已经证明，在 LPS 诱导的内毒素休克小鼠模型中，用 pan-PAD 抑制剂同时抑制 PAD2 和 PAD4 可以减少 NETosis 并提高存活率。然而，人们对 NETosis 和内毒素休克期间 PAD2 特异性抑制的影响知之甚少。因此，在本研究中，我们旨在研究特定 PAD2 或 PAD4 抑制剂对 LPS 诱导的小鼠内毒素休克的影响。我们发现 PAD2 抑制而非 PAD4 抑制可提高存活率。此外，PAD2 抑制剂显着降低了促炎细胞因子和 NETosis 的水平。据我们所知，这项研究首次证明 PAD2 抑制可以减少 NETosis，减少炎性细胞因子的产生，并防止内毒素诱导的致死性。我们的研究结果为治疗内毒素休克提供了一种新的治疗策略。