Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice.
Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice.
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DOI：
10.3389/fimmu.2022.984298
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发表时间：
2022
影响因子：
7.3
通讯作者：
Zingarelli, Basilia
中科院分区：
文献类型：
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作者：
Urban, Catherine;Hayes, Hannah V.;Piraino, Giovanna;Wolfe, Vivian;Lahni, Patrick;O'Connor, Michael;Phares, Ciara;Zingarelli, Basilia
内皮功能障碍在脓毒症介导的多器官功能衰竭的发病机制中起核心作用。一些临床和实验研究表明，糖萼是感染期间内皮损伤的早期靶点。Colivelin是线粒体肽humanin的合成衍生物，在氧化条件下显示出细胞保护作用。在目前的研究中，我们的目的是确定潜在的治疗作用colivelin在内皮功能障碍和脓毒症的结果在体内。雄性C57 BL/6小鼠通过盲肠结扎和穿刺（CLP）进行临床相关的多微生物脓毒症模型，并在CLP后1 h腹腔内给予溶媒或大肠菌素（100-200 µg/kg）。我们观察到，与对照组小鼠相比，溶剂处理的小鼠在CLP后6小时具有粘附分子ICAM-1和P-选择素、血管生成因子内皮糖蛋白和糖萼多配体蛋白聚糖-1的血浆水平的早期升高，而血管生成素-2（微血管崩解的介质）和前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（与内毒素清除有关的酶）的水平，CLP后18 h升高。这些内皮和糖萼损伤生物标志物的早期升高与肺、肝和肾中的肺组织学损伤和中性粒细胞炎症一致。在透射电子显微镜分析中，脓毒症小鼠的胸部脓肿显示糖萼分解和脱落增加，内皮细胞和平滑肌细胞中的线粒体受损。Colivelin治疗改善了肺结构，减少了器官中性粒细胞浸润，并降低了syndecan-1、肿瘤坏死因子-α、巨噬细胞炎性蛋白-1 α和白细胞介素-10的血浆水平。Colivelin的这些治疗作用与主动脉中糖萼密度和线粒体结构的改善相关。在分子分析中，colivelin治疗与主动脉和肺中信号转导子和转录激活子3的抑制以及AMP活化蛋白激酶的激活相关。在长达7天的长期结局研究中，与单独使用抗生素治疗相比，Colivelin与抗菌药物联合治疗显著降低了疾病严重程度评分。总之，我们的数据支持糖萼损伤是脓毒症的早期发病事件，colivelin可能具有治疗脓毒症相关的内皮功能障碍的治疗潜力。
Endothelial dysfunction plays a central role in the pathogenesis of sepsis-mediated multiple organ failure. Several clinical and experimental studies have suggested that the glycocalyx is an early target of endothelial injury during an infection. Colivelin, a synthetic derivative of the mitochondrial peptide humanin, has displayed cytoprotective effects in oxidative conditions. In the current study, we aimed to determine the potential therapeutic effects of colivelin in endothelial dysfunction and outcomes of sepsis in vivo. Male C57BL/6 mice were subjected to a clinically relevant model of polymicrobial sepsis by cecal ligation and puncture (CLP) and were treated with vehicle or colivelin (100-200 µg/kg) intraperitoneally at 1 h after CLP. We observed that vehicle-treated mice had early elevation of plasma levels of the adhesion molecules ICAM-1 and P-selectin, the angiogenetic factor endoglin and the glycocalyx syndecan-1 at 6 h after CLP when compared to control mice, while levels of angiopoietin-2, a mediator of microvascular disintegration, and the proprotein convertase subtilisin/kexin type 9, an enzyme implicated in clearance of endotoxins, raised at 18 h after CLP. The early elevation of these endothelial and glycocalyx damage biomarkers coincided with lung histological injury and neutrophil inflammation in lung, liver, and kidneys. At transmission electron microscopy analysis, thoracic aortas of septic mice showed increased glycocalyx breakdown and shedding, and damaged mitochondria in endothelial and smooth muscle cells. Treatment with colivelin ameliorated lung architecture, reduced organ neutrophil infiltration, and attenuated plasma levels of syndecan-1, tumor necrosis factor-α, macrophage inflammatory protein-1α and interleukin-10. These therapeutic effects of colivelin were associated with amelioration of glycocalyx density and mitochondrial structure in the aorta. At molecular analysis, colivelin treatment was associated with inhibition of the signal transducer and activator of transcription 3 and activation of the AMP-activated protein kinase in the aorta and lung. In long-term outcomes studies up to 7 days, co-treatment of colivelin with antimicrobial agents significantly reduced the disease severity score when compared to treatment with antibiotics alone. In conclusion, our data support that damage of the glycocalyx is an early pathogenetic event during sepsis and that colivelin may have therapeutic potential for the treatment of sepsis-associated endothelial dysfunction.
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影响因子：
--
作者：
Dounousi E;Tellis C;Pavlakou P;Duni A;Liakopoulos V;Mark PB;Papagianni A;Tselepis AD
通讯作者：
Tselepis AD
影响因子：
3.3
作者：
Sari, Y.;Chiba, T.;Yamada, M.;Rebeca, G. V.;Aiso, S.
通讯作者：
Aiso, S.
影响因子：
5.8
作者：
Agouridakis P;Kyriakou D;Alexandrakis MG;Prekates A;Perisinakis K;Karkavitsas N;Bouros D
通讯作者：
Bouros D
DOI：
10.1097/01.pcc.0000074583.27727.8e
发表时间：
2003-07-01
期刊：
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
影响因子：
--
作者：
Flori, Heidi R;Ware, Lorraine B;Matthay, Michael A
通讯作者：
Matthay, Michael A
影响因子：
16.6
作者：
Balic, Jesse J.;Albargy, Hassan;Mansell, Ashley
通讯作者：
Mansell, Ashley