Additional benefit of combined therapy with melatonin and apoptotic adipose-derived mesenchymal stem cell against sepsis-induced kidney injury
Additional benefit of combined therapy with melatonin and apoptotic adipose-derived mesenchymal stem cell against sepsis-induced kidney injury
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DOI：
10.1111/jpi.12140
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发表时间：
2014-08-01
影响因子：
10.3
通讯作者：
Yip, Hon-Kan
中科院分区：
文献类型：
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作者：
Chen, Hong-Hwa;Lin, Kun-Chen;Yip, Hon-Kan
本研究测试了褪黑激素和凋亡脂肪间充质干细胞（A-ADMSCs）的联合治疗是否在改善脓毒症诱导的急性肾损伤方面提供了额外的益处。将成年雄性Sprague-Dawley大鼠（n = 65）平均随机分为五组：假手术对照组（SC）、盲肠结扎和穿刺（CLP）诱导的脓毒症组、CLP-褪黑激素组、CLP-A-ADMSC组和CLP-褪黑激素-A-ADMSC组。CLP后6小时循环TNF-α水平CLP组最高，SC组最低，CLP-褪黑素组高于CLP-A-ADMSC组和CLP-褪黑素-A-ADMSC组（均P < 0.001）。在CLP后72小时，脾辅助性T细胞、细胞毒性T细胞和调节性T细胞的数量反映的免疫反应性在所有组中表现出与循环TNF-α相同的模式（P < 0.001）。CLP组肾组织损伤评分、F4/80+细胞和CD 14+细胞数最高，SC组最低，CLP-褪黑素组高于CLP-A-ADMSC组和CLP-褪黑素-ADMSC组，CLP-A-ADMSC组高于CLP-褪黑素-ADMSC组（均P < 0.001）。炎症（RANTES、TNF-1 α、NF-κ B、MMP-9、MIP-1、IL-1 β）、凋亡（切割的caspase 3和PARP、线粒体Bax）、纤维化（Smad 3、TGF-β）标志物、活性氧（NOX-1、NOX-2）和氧化应激的蛋白表达变化在5组中显示与肾损伤评分相同的模式（均P < 0.001）。抗氧化剂（GR+、GPx+、HO-1、NQO-1+）的表达在SC组最低，在CLP-褪黑素-A-ADMSC组最高，在CLP组低于CLP-褪黑素组和CLP-A-ADMSC组，在CLP-褪黑素-ADMSC组低于CLP-A-ADMSC组（均P < 0.001）。总之，褪黑素和A-ADMSC的联合治疗在保护肾脏免受脓毒症诱导的损伤方面优于单独的A-ADMSC上级。
This study tested whether combined therapy with melatonin and apoptotic adipose-derived mesenchymal stem cells (A-ADMSCs) offered additional benefit in ameliorating sepsis-induced acute kidney injury. Adult male Sprague-Dawley rats (n = 65) were randomized equally into five groups: Sham controls (SC), sepsis induced by cecal-ligation and puncture (CLP), CLP-melatonin, CLP-A-ADMSC, and CLP-melatonin-A-ADMSC. Circulating TNF-alpha level at post-CLP 6 hr was highest in CLP and lowest in SC groups, higher in CLP-melatonin than in CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups (all P < 0.001). Immune reactivity as reflected in the number of splenic helper-, cytoxic-, and regulatory-T cells at post-CLP 72 hr exhibited the same pattern as that of circulating TNF-alpha among all groups (P < 0.001). The histological scoring of kidney injury and the number of F4/80+ and CD14+ cells in kidney were highest in CLP and lowest in SC groups, higher in CLP-melatonin than in CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups, and higher in CLP-A-ADMSC than in CLP-melatonin-A-ADMSC groups (all P < 0.001). Changes in protein expressions of inflammatory (RANTES, TNF-1 alpha, NF-kappa B, MMP-9, MIP-1, IL-1 beta), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF-beta) markers, reactive-oxygen-species (NOX-1, NOX-2), and oxidative stress displayed a pattern identical to that of kidney injury score among the five groups (all P < 0.001). Expressions of antioxidants (GR+, GPx+, HO-1, NQO-1+) were lowest in SC group and highest in CLP-melatonin-A-ADMSC group, lower in CLP than in CLP-melatonin and CLP-A-ADMSC groups, and lower in CLP-melatonin-than in CLP-A-ADMSC-tretaed animals (all P < 0.001). In conclusion, combined treatment with melatonin and A-ADMSC was superior to A-ADMSC alone in protecting the kidneys from sepsis-induced injury.