PDF(Pubmed)
Abstract：
Endothelial hyperpermeability is pivotal in sepsis-associated multi-organ dysfunction. Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin αvβ3, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis. Recently, we identified isaridin E (ISE), a marine-derived fungal cyclohexadepsipeptide, as a promising antiplatelet and antithrombotic agent with a low bleeding risk. ISE\'s influence on septic mortality and sepsis-induced lung injury in a mouse model of sepsis, induced by caecal ligation and puncture, is investigated in this study. ISE dose-dependently improved survival rates, mitigating lung injury, thrombocytopenia, pulmonary endothelial permeability, and vascular inflammation in the mouse model. ISE markedly curtailed vWF release from activated platelets in septic mice by suppressing vesicle-associated membrane protein 8 and soluble N-ethylmaleide-sensitive factor attachment protein 23 overexpression. Moreover, ISE inhibited healthy human platelet adhesion to cultured lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), thereby significantly decreasing vWF secretion and endothelial hyperpermeability. Using cilengitide, a selective integrin αvβ3 inhibitor, it was found that ISE can improve endothelial hyperpermeability by inhibiting vWF binding to αvβ3. Activation of the integrin αvβ3-FAK/Src pathway likely underlies vWF-induced endothelial dysfunction in sepsis. In conclusion, ISE protects against sepsis by inhibiting endothelial hyperpermeability and platelet-endothelium interactions.
摘要：
内皮高通透性是脓毒症相关多器官功能障碍的关键。增加血管性血友病因子(vWF)血浆水平，源于脓毒症期间活化的血小板和内皮损伤，可与整合素αvβ3结合，加剧内皮通透性。因此，靶向该途径为脓毒症提供了潜在的治疗途径.最近,我们鉴定了isaridinE(ISE)，一种海洋真菌环己肽，作为一种有前途的抗血小板和抗血栓药物，出血风险低。ISE对脓毒症小鼠模型脓毒症死亡率和脓毒症肺损伤的影响,盲肠结扎和穿刺诱导，在这项研究中进行了调查。ISE剂量依赖性地提高生存率，减轻肺损伤，血小板减少症,肺内皮通透性,和小鼠模型中的血管炎症。ISE通过抑制囊泡相关膜蛋白8和可溶性N-乙基马来酰亚胺敏感因子附着蛋白23的过度表达，显着减少了脓毒症小鼠活化血小板中vWF的释放。此外，ISE抑制健康人血小板对培养的脂多糖（LPS）刺激的人脐静脉内皮细胞（HUVECs）的粘附，从而显著降低vWF分泌和内皮高通透性。使用cilengitide,选择性整合素αvβ3抑制剂，发现ISE可以通过抑制vWF与αvβ3的结合来改善内皮通透性。整合素αvβ3-FAK/Src途径的激活可能是vWF诱导的脓毒症内皮功能障碍的基础。总之,ISE通过抑制内皮高通透性和血小板-内皮相互作用来预防脓毒症。
