ANGIOGENESIS INHIBITOR ENDOSTATIN PROTECTS MICE WITH SEPSIS FROM MULTIPLE ORGAN DYSFUNCTION SYNDROME
ANGIOGENESIS INHIBITOR ENDOSTATIN PROTECTS MICE WITH SEPSIS FROM MULTIPLE ORGAN DYSFUNCTION SYNDROME
复制标题
血管生成抑制剂内皮抑素可保护脓毒症小鼠免受多器官功能障碍综合征的影响
DOI：
10.1097/shk.0000000000000427
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发表时间：
2015-10-01
期刊：
影响因子：
3.1
通讯作者：
Xiao, Xianzhong
中科院分区：
文献类型：
--
作者：
Peng, Yue;Gao, Min;Xiao, Xianzhong
内皮抑素是血管内皮细胞的内源性抑制物。它能抑制内皮细胞的迁移、增殖和血管生成，主要用于抗癌治疗。我们已发现内皮抑素是脓毒症发病机制中的重要节点蛋白。然而，其对脓毒症的影响尚未见报道。采用盲肠结扎穿刺术(CLP)建立脓毒症小鼠模型，给予内皮抑素或安慰剂(生理盐水)。观察内皮抑素对血清酶、伊文思蓝渗漏、肺湿/干质量比和细胞因子(肿瘤坏死因子α、白介素1β[IL-1β]、白介素6)产生的影响。观察3天内的存活率。此外，我们还观察了内皮抑素对脓毒症小鼠血清血管内皮生长因子A(VEGF-A)、血管内皮生长因子-C(VEGF-C)、肺组织病理改变和评分以及肺组织中JNK、p38和Erk1/2蛋白的磷酸化的影响。我们发现，内皮抑素可以时间和剂量依赖的方式提高脓毒症小鼠的存活率，可能是通过减少血清指标、形态学变化、伊文斯蓝渗漏、湿/干重比和肺组织炎症等多器官功能障碍来实现的。此外，内皮抑素还能降低脓毒症小鼠血清肿瘤坏死因子α、IL-1β、IL-6和血管内皮生长因子C的水平，并抑制脓毒症小鼠肺组织中p38和ERK1/2的磷酸化。本研究首次从抑制炎症反应、阻断血管内皮生长因子受体、抑制血管内皮生长因子C表达、降低血管通透性等方面阐明了内皮抑素对脓毒症的保护作用及其可能的机制。总体而言，这项研究揭示了内皮抑素在脓毒症治疗中的潜在保护作用。
Endostatin is an endogenous inhibitor of vascular endothelium. It can inhibit endothelial cell migration, proliferation, and vascular angiogenesis and is mainly used for anticancer therapy. We have previously found that endostatin is an important node protein in the pathogenesis of sepsis. However, its impacts on sepsis have not yet been reported. We established a septic mouse model using cecal ligation and puncture (CLP) and gave the mice either endostatin or placebo (saline). The effects of endostatin on serum enzyme, Evans blue leakage, lung wet-to-dry weight ratio, and cytokine (tumor necrosis factor a, interleukin 1 beta [IL-1 beta], and IL-6) production were assessed. Survival rates were observed for up to 3 days. In addition, we examined the effects of endostatin on serum vascular endothelial growth factor A (VEGF-A), VEGF-C, and pathological changes and scores of lung tissues as well as the phosphorylation of JNK, p38, and ERKl/2 proteins in lung tissues of mice with sepsis. We found that endostatin can increase the survival of septic mice in a time-and dose-dependent manner probably by reducing multiorgan dysfunctions shown by serum indicators, morphologic changes, Evans blue leakage, wet-to-dry weight ratio, and inflammation of lung tissues. In addition, endostatin could reduce serum tumor necrosis factor alpha, IL-1 beta, IL-6, and VEGF-C levels in septic mice as well as inhibit phosphorylation of p38 and ERK1/2 in lung tissues of septic mice. This is the first study demonstrating the protective effect of endostatin on sepsis and its possible underlying mechanisms from the aspects of inhibiting inflammatory responses, blocking VEGF receptor, attenuating VEGF-C expression, and reducing vascular permeability. Overall, the study revealed the potential protect role for endostatin in the treatment of sepsis.