Division of Colon and Rectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan.
Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan.
Am J Transl Res. 2014 Oct 11;6(5):439-58. eCollection 2014.
This study investigated whether combining melatonin and apoptotic adipose-derived mesenchymal stem cells (A-ADMSC) was superior to ADMSC alone in ameliorating sepsis-induced acute lung injury. Adult male Sprague-Dawley rats (n=50) 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 interleukin (IL)-6 at 6, 18, and 72 hrs, were highest in CLP and lowest in SC groups, higher in CLP-melatonin than CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups, higher in CLP-A-ADMSC than CLP-melatonin-A-ADMSC groups (all p<0.001). Immune reactivity (indicated by circulating cytotoxic-, and regulatory-T cells) and WBC count at 72 h exhibited the same pattern as that of circulating IL-6 (all p<0.001). Changes in histological scoring of lung parenchyma and the number of CD68+ and CD14+ cells showed a similar pattern compared to that of IL-6 level in all groups (all p<0.001). Changes in protein expressions of inflammatory (oxidative stress, RANTES, TNF-α, NF-κB, MMP-9, MIP-1, IL-1β), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF-β) markers and those of reactive-oxygen-species (NOX-1, NOX-2) displayed an identical pattern compared to that of circulating IL-6 in all groups (all p<0.001). Anti-oxidative capacities (GR+, GPx+, HO-1, NQO-1+) and angiogenesis marker (CXCR4+ cells) were lowest in SC group but highest in CLP-melatonin-A-ADMSC group, lower in CLP than CLP-melatonin and CLP-A-ADMSC groups, and lower in CLP-melatonin than CLP-A-ADMSC groups (all p<0.001). In conclusion, combined melatonin and A-ADMSC were superior to A-ADMSC alone in protecting the lung from sepsis-induced injury.
这项研究旨在探讨褪黑素与凋亡脂肪间充质干细胞（A-ADMSC）联合应用是否优于单独应用 ADMSC 改善脓毒症诱导的急性肺损伤。将成年雄性 Sprague-Dawley 大鼠（n=50）随机等分为五组：假手术对照组（SC）、盲肠结扎穿孔术（CLP）诱导的脓毒症组、CLP 联合褪黑素组、CLP 联合 A-ADMSC 组、CLP 联合褪黑素和 A-ADMSC 组。结果显示，与 SC 组相比，CLP 组大鼠外周血白细胞介素（IL）-6 在 6、18 和 72 小时时最高，而 SC 组最低；CLP 联合褪黑素组高于 CLP 联合 A-ADMSC 组和 CLP 联合褪黑素和 A-ADMSC 组，CLP 联合 A-ADMSC 组高于 CLP 联合褪黑素和 A-ADMSC 组（均 p<0.001）。72 小时时的免疫反应性（以循环细胞毒性和调节性 T 细胞表示）和白细胞计数也表现出与循环 IL-6 相同的模式（均 p<0.001）。肺实质组织学评分的变化以及 CD68+和 CD14+细胞的数量与各组 IL-6 水平的变化模式相似（均 p<0.001）。所有组中，炎症标志物（氧化应激、RANTES、TNF-α、NF-κB、MMP-9、MIP-1、IL-1β）、凋亡标志物（cleaved caspase 3 和 PARP、线粒体 Bax）、纤维化标志物（Smad3、TGF-β）和活性氧（NOX-1、NOX-2）的蛋白表达变化与循环 IL-6 水平的变化模式相似（均 p<0.001）。抗氧化能力（GR+、GPx+、HO-1、NQO-1+）和血管生成标志物（CXCR4+细胞）在 SC 组中最低，在 CLP 联合褪黑素和 A-ADMSC 组中最高，在 CLP 组中低于 CLP 联合褪黑素组和 CLP 联合 A-ADMSC 组，在 CLP 联合褪黑素组中低于 CLP 联合 A-ADMSC 组（均 p<0.001）。综上所述，褪黑素与 A-ADMSC 联合应用优于单独应用 A-ADMSC，可更有效地保护肺免受脓毒症诱导的损伤。
