Department of Nephrology & Hypertension, Hannover Medical School, Carl-NeubergStrasse1, D- 30625, Hannover, Germany.
Cytokine. 2011 Aug;55(2):251-9. doi: 10.1016/j.cyto.2011.04.005. Epub 2011 Apr 30.
Endothelial activation leading to vascular barrier breakdown plays an essential role in the pathophysiology of multiple-organ dysfunction syndrome (MODS) in sepsis. Increasing evidence suggests that the function of the vessel-protective factor Angiopoietin-1 (Ang-1), a ligand of the endothelial-specific Tie2 receptor, is inhibited by its antagonist Angiopoietin-2 (Ang-2) during sepsis. In order to reverse the effects of the sepsis-induced suppression of Ang-1 and elevation of Ang-2 we aimed to investigate whether an intravenous injection of recombinant human (rh) Ang-1 protects against MODS in murine sepsis.
Polymicrobiological abdominal sepsis was induced by cecal ligation and puncture (CLP). Mice were treated with either 1 μg of intravenous rhAng-1 or control buffer immediately after CLP induction and every 8h thereafter. Sham-operated animals served as time-matched controls.
Compared to buffer-treated controls, rhAng-1 treated septic mice showed significant improvements in several hematologic and biochemical indicators of MODS. Moreover, rhAng-1 stabilized endothelial barrier function, as evidenced by inhibition of protein leakage from lung capillaries into the alveolar compartment. Histological analysis revealed that rhAng-1 treatment attenuated leukocyte infiltration in lungs and kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression in rhAng-1 treated mice. Finally, the protective effects of rhAng-1 treatment were reflected by an improved survival time in a lethal CLP model.
In a clinically relevant murine sepsis model, intravenous rhAng-1 treatment alone is sufficient to significantly improve a variety of sepsis-associated organ dysfunctions and survival time, most likely by preserving endothelial barrier function. Further studies are needed to pave the road for clinical application of this therapy concept.
内皮细胞激活导致血管屏障破裂在脓毒症多器官功能障碍综合征（MODS）的病理生理学中起着重要作用。越来越多的证据表明，血管保护因子血管生成素-1（Ang-1）的功能在脓毒症中被其拮抗剂血管生成素-2（Ang-2）抑制。为了逆转脓毒症引起的 Ang-1抑制和 Ang-2 升高的影响，我们旨在研究静脉注射重组人（rh）Ang-1是否能预防小鼠脓毒症中的 MODS。
通过盲肠结扎和穿刺（CLP）诱导多微生物性腹部脓毒症。CLP 诱导后立即给予小鼠 1μg 静脉注射 rhAng-1 或对照缓冲液，并每 8 小时给予一次。假手术动物作为时间匹配的对照。
与缓冲液治疗的对照组相比，rhAng-1 治疗的脓毒症小鼠多项 MODS 的血液学和生化指标显著改善。此外，rhAng-1 稳定了内皮屏障功能，表现为抑制肺毛细血管蛋白渗漏到肺泡腔。组织学分析表明，rhAng-1 治疗减轻了脓毒症小鼠肺部和肾脏的白细胞浸润，这可能是由于 rhAng-1 治疗小鼠内皮细胞黏附分子表达减少所致。最后，rhAng-1 治疗的保护作用反映在致命性 CLP 模型中存活时间的延长。
在一种临床相关的小鼠脓毒症模型中，单独静脉注射 rhAng-1 就足以显著改善多种与脓毒症相关的器官功能障碍和存活时间，这很可能是通过维持内皮屏障功能实现的。需要进一步的研究为这种治疗概念的临床应用铺平道路。
