Sepsis is an infection-induced aggressive and life-threatening organ dysfunction with high morbidity and mortality worldwide. Infection-associated inflammation and coagulation promote the progression of adverse outcomes in sepsis. Here, we report that phospho-Tyr705 of STAT3 (pY-STAT3), not total STAT3, contributes to systemic inflammation and coagulopathy in sepsis. Cecal ligation and puncture (CLP)-induced septic mice were treated with BP-1-102, Napabucasin, or vehicle control respectively and then assessed for systemic inflammation, coagulation response, lung function and survival. Human pulmonary microvascular endothelial cells (HPMECs) and Raw264.7 cells were exposed to lipopolysaccharide (LPS) with pharmacological or genetic inhibition of pY-STAT3. Cells were assessed for inflammatory and coagulant factor expression, cell function and signaling. Pharmacological inhibition of pY-STAT3 expression by BP-1-102 reduced the proinflammatory factors, suppressed coagulation activation, attenuated lung injury, alleviated vascular leakage and improved the survival rate in septic mice. Pharmacological or genetic inhibition of pY-STAT3 diminished LPS-induced cytokine production in macrophages and protected pulmonary endothelial cells via the IL-6/JAK2/STAT3, NF-κB and MAPK signaling pathways. Moreover, the increase in procoagulant indicators induced by sepsis such as tissue factor (TF), the thrombin-antithrombin complex (TAT) and D-Dimer were down-regulated by pY-STAT3 inhibition. Our results revealed a therapeutic role of pY-STAT3 in modulating the inflammatory response and defective coagulation during sepsis.

中文翻译：

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STAT3 的磷酸化 Tyr705 是通过调节炎症和凝血来治疗脓毒症的靶点。

脓毒症是一种感染引起的侵袭性和危及生命的器官功能障碍，在全世界范围内具有很高的发病率和死亡率。感染相关的炎症和凝血会促进脓毒症不良后果的进展。在这里，我们报告 STAT3 的磷酸化 Tyr705 (pY-STAT3)，而不是总 STAT3，导致脓毒症中的全身炎症和凝血病。分别用 BP-1-102、Napabucasin 或载体对照治疗盲肠结扎穿刺 (CLP) 诱导的脓毒症小鼠，然后评估全身炎症、凝血反应、肺功能和存活率。将人肺微血管内皮细胞 (HPMEC) 和 Raw264.7 细胞暴露于脂多糖 (LPS)，对 pY-STAT3 进行药理或遗传抑制。评估细胞的炎症和凝血因子表达、细胞功能和信号传导。BP-1-102对pY-STAT3表达的药理学抑制可减少促炎因子、抑制凝血激活、减轻肺损伤、减轻血管渗漏并提高脓毒症小鼠的存活率。pY-STAT3 的药理学或遗传抑制可减少巨噬细胞中 LPS 诱导的细胞因子产生，并通过 IL-6/JAK2/STAT3、NF-κB 和 MAPK 信号通路保护肺内皮细胞。此外，脓毒症引起的促凝血指标如组织因子（TF）、凝血酶-抗凝血酶复合物（TAT）和D-二聚体的增加被pY-STAT3抑制下调。我们的结果揭示了 pY-STAT3 在调节脓毒症期间炎症反应和凝血缺陷方面的治疗作用。