Song J W, Zullo J A, Liveris D, Dragovich M, Zhang X F, Goligorsky M S
Renal Research Institute and Departments of Medicine, Pharmacology and Physiology (J.A.Z., M.S.G.), and Department of Microbiology (D.L.), New York Medical College, Valhalla, New York; Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, South Korea (J.W.S.); and Department of Mechanical Engineering and Mechanics, and Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania (M.D., X.F.Z.)
Renal Research Institute and Departments of Medicine, Pharmacology and Physiology (J.A.Z., M.S.G.), and Department of Microbiology (D.L.), New York Medical College, Valhalla, New York; Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, South Korea (J.W.S.); and Department of Mechanical Engineering and Mechanics, and Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania (M.D., X.F.Z.).
J Pharmacol Exp Ther. 2017 Apr;361(1):115-121. doi: 10.1124/jpet.116.239509. Epub 2017 Feb 6.
Endothelial glycocalyx (EG) is disintegrated during sepsis. We have previously shown that this occurs very early in the course of sepsis and its prevention improves the survival of mice with sepsis. Here, we sought to investigate the possibility of pharmacologically accelerating the restoration of disintegrated EG in sepsis. We used a soilage injection model to induce polymicrobial sepsis in C57/BL6 mice and measured total body EG. En face aortic preparations were used for staining of markers of EG and atomic force microscopy was used to measure EG in vitro. In vitro studies were conducted in cultured endothelial cells either exposed to a lipopolysaccharide or enzymatically denuded of EG. Sulodexide (SDX), a heparin sulfate-like compound resistant to degradation by heparanase, accelerated EG regeneration in vitro and in vivo. The total volume of EG was drastically reduced in septic mice. Administration of SDX produced a dramatic acceleration of EG restoration. This effect, unrelated to any SDX-induced differences in microbial burden, was associated with better control of vascular permeability. Notably, SDX demonstrated not only a remarkable capacity for EG regeneration in vitro and in vivo but was also associated with improved animal survival, even when instituted 2 hours after induction of severe sepsis. In conclusion, 1) EG is disintegrated in sepsis, the event which contributes to high animal mortality; 2) pharmacologic acceleration of EG restoration can be achieved using SDX; and 3) SDX reduces vascular permeability, which is elevated in septic mice, and improves animal survival.
内皮糖萼（EG）在脓毒症期间会解体。我们之前已经表明，这种情况在脓毒症病程中很早就会发生，并且预防这种情况可提高脓毒症小鼠的存活率。在此，我们试图研究通过药物加速脓毒症中解体的EG恢复的可能性。我们使用粪便注射模型在C57/BL6小鼠中诱导多微生物脓毒症，并测量全身EG。采用主动脉标本进行EG标志物染色，并使用原子力显微镜在体外测量EG。体外研究在暴露于脂多糖或经酶法去除EG的培养内皮细胞中进行。舒洛地昔（SDX）是一种对乙酰肝素酶降解具有抗性的硫酸肝素样化合物，可在体外和体内加速EG再生。脓毒症小鼠中EG的总体积大幅减少。给予SDX可显著加速EG的恢复。这种效应与SDX引起的微生物负荷差异无关，与更好地控制血管通透性有关。值得注意的是，SDX不仅在体外和体内具有显著的EG再生能力，而且即使在严重脓毒症诱导后2小时开始使用，也与动物存活率提高有关。总之，1）EG在脓毒症中解体，这一事件导致动物高死亡率；2）使用SDX可实现EG恢复的药物加速；3）SDX可降低脓毒症小鼠中升高的血管通透性，并提高动物存活率。
