The synthetic Tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis
The synthetic Tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis
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DOI：
10.1186/cc10523
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发表时间：
2011-01-01
期刊：
影响因子：
15.1
通讯作者：
Shushakova, Nelli
中科院分区：
文献类型：
--
作者：
Kuempers, Philipp;Gueler, Faikah;Shushakova, Nelli
前言：血管生成素-1(Angpt1)是内皮细胞Tie2受体的天然激动剂配体，是一种非冗余的内皮存活和血管稳定因子，可降低内皮通透性，抑制白细胞与内皮细胞的相互作用。在这里，我们评估了一种新型聚乙二醇簇Tie2激动肽(VT)对多菌腹腔炎小鼠模型血管渗漏和死亡率的保护作用。方法：采用盲肠结扎穿刺法(CLP)诱导C57BL6小鼠多菌性腹壁脓毒症。用不同剂量的VT或等体积的磷酸盐缓冲盐水(PBS)处理小鼠。结果：VT全身给药可在体内诱导持续的Tie2激活。VT对脓毒症诱导的内皮屏障功能障碍具有保护作用，其证据是血管渗漏和白细胞向腹膜腔内迁移的减少。组织学分析显示，VT治疗改善了脓毒症小鼠肾脏中的白细胞渗透，可能是由于减少了内皮细胞黏附分子的表达。室速驱动的效应与器官功能的显著改善和循环细胞因子水平的降低有关。VT的内皮特异性作用得到了其他体外研究的支持，这些研究表明VT对分离的腹膜巨噬细胞释放的细胞因子或分离的中性粒细胞的迁移能力没有影响。最后，CLP前给予VT(危险比0.39[95%可信区间0.19-0.81]P&t；0.001)和CLP后给予VT降低败血症小鼠死亡率(HR 0.22[95%CI 0.06-0.83]P<；0.05)。结论：在临床相关的小鼠脓毒症模型中，我们提供了有效使用PEGylated VT(一种药物样Tie2受体激动剂)对抗微血管内皮细胞屏障功能障碍和降低死亡率的原则证据。需要进一步的研究为这一治疗概念的临床应用铺平道路。
Introduction: Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Here we evaluate the efficacy of a novel polyethylene glycol (PEG)-clustered Tie2 agonist peptide, vasculotide (VT), to protect against vascular leakage and mortality in a murine model of polymicrobial abdominal sepsis.Methods: Polymicrobial abdominal sepsis in C57BL6 mice was induced by cecal-ligation-and-puncture (CLP). Mice were treated with different dosages of VT or equal volume of phosphate-buffered saline (PBS). Sham-operated animals served as time-matched controls.Results: Systemic administration of VT induced long-lasting Tie2 activation in vivo. VT protected against sepsis-induced endothelial barrier dysfunction, as evidenced by attenuation of vascular leakage and leukocyte transmigration into the peritoneal cavity. Histological analysis revealed that VT treatment ameliorated leukocyte infiltration in kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression. VT-driven effects were associated with significantly improved organ function and reduced circulating cytokine levels. The endothelial-specific action of VT was supported by additional in vitro studies showing no effect of VT on either cytokine release from isolated peritoneal macrophages, or migratory capacity of isolated neutrophils. Finally, administration of VT pre-CLP (hazard ratio 0.39 [95% confidence interval 0.19-0.81] P < 0.001) and post-CLP reduced mortality in septic mice (HR 0.22 [95% CI 0.06-0.83] P < 0.05).Conclusions: We provide proof of principle in support of the efficacious use of PEGylated VT, a drug-like Tie2 receptor agonist, to counteract microvascular endothelial barrier dysfunction and reduce mortality in a clinically relevant murine sepsis model. Further studies are needed to pave the road for clinical application of this therapeutic concept.