Abstract：
Sepsis-induced acute lung injury (SALI) is the common complication of sepsis, resulting in high incidence and mortality rates. The primary pathogenesis of SALI is the interplay between acute inflammation and endothelial barrier damage. Studies have shown that kaempferol (KPF) has anti-sepsis properties. Sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling pathway\'s significance in acute lung damage and S1P receptor 1 (S1PR1) agonists potential in myosin light chain 2 (MLC2) phosphorylation are documented. Whether KPF can regulate the SphK1/S1P/S1PR1/MLC2 signaling pathway to protect the lung endothelial barrier remains unclear. This study investigates the KPF\'s therapeutic effects and molecular mechanisms in repairing endothelial cell barrier damage in both LPS-induced sepsis mice and human umbilical vein endothelial cells (HUVECs). KPF significantly reduced lung tissue damage and showed anti-inflammatory effects by decreasing IL-6 and TNF-α synthesis in the sepsis mice model. Further, KPF administration can reduce the high permeability of the LPS-induced endothelial cell barrier and alleviate lung endothelial cell barrier injury. Mechanistic studies showed that KPF pretreatment can suppress MLC2 hyperphosphorylation and decrease SphK1, S1P, and S1PR1 levels. The SphK1/S1P/S1PR1/MLC2 signaling pathway controls the downstream proteins linked to endothelial barrier damage, and the Western blot (WB) showed that KPF raised the protein levels. These proteins include zonula occludens (ZO)-1, vascular endothelial (VE)-cadherin and Occludin. The present work revealed that in mice exhibiting sepsis triggered by LPS, KPF strengthened the endothelial barrier and reduced the inflammatory response. The SphK1/S1P/S1PR1/MLC2 pathway\'s modulation is the mechanism underlying this impact.
摘要：
脓毒症诱导的急性肺损伤(SALI)是脓毒症的常见并发症,导致高发病率和死亡率。SALI的主要发病机制是急性炎症和内皮屏障损伤之间的相互作用。研究表明山奈酚(KPF)具有抗脓毒症作用。鞘氨醇激酶1（Sphk1）/鞘氨醇-1-磷酸（S1P）信号通路在急性肺损伤和S1P受体1（S1PR1）激动剂在肌球蛋白轻链2（MLC2）磷酸化中的潜在意义。KPF是否能调节SphK1/S1P/SIPR1/MLC2信号通路保护肺内皮屏障尚不清楚。本研究探讨了KPF对LPS诱导的脓毒症小鼠和人脐静脉内皮细胞(HUVECs)内皮细胞屏障损伤的修复作用及其分子机制。在脓毒症小鼠模型中,KPF通过降低IL-6和TNF-α的合成显著减轻肺组织损伤并显示抗炎作用。Further,KPF可降低LPS诱导的内皮细胞屏障的高通透性,减轻肺内皮细胞屏障损伤。机制研究表明，KPF预处理可以抑制MLC2过度磷酸化，降低SphK1、S1P、和S1PR1级别。SphK1/S1P/S1PR1/MLC2信号通路控制与内皮屏障损伤相关的下游蛋白，蛋白质印迹（WB）显示KPF升高了蛋白质水平。这些蛋白质包括闭塞带（ZO）-1，血管内皮（VE）-钙黏着蛋白和Occludin。目前的工作表明，在表现出由LPS引发的败血症的小鼠中，KPF加强了内皮屏障，减轻了炎症反应。SphK1/S1P/S1PR1/MLC2通路的调节是这种影响的潜在机制。
