Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.
Crit Care Med. 2021 Sep 1;49(9):e880-e890. doi: 10.1097/CCM.0000000000005056.
To ascertain whether systemic administration of mitochondria-rich fraction isolated from mesenchymal stromal cells would reduce lung, kidney, and liver injury in experimental sepsis.
Animal study.
Laboratory investigation.
Sixty C57BL/6 male mice.
Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. At 24 hours after surgery, cecal ligation and puncture and Sham animals were further randomized to receive saline or mitochondria-rich fraction isolated from mesenchymal stromal cells (3 × 106) IV. At 48 hours, survival, peritoneal bacterial load, lung, kidney, and liver injury were analyzed. Furthermore, the effects of mitochondria on oxygen consumption rate and reactive oxygen species production of lung epithelial and endothelial cells were evaluated in vitro.
In vitro exposure of lung epithelial and endothelial cells from cecal ligation and puncture animals to mitochondria-rich fraction isolated from mesenchymal stromal cells restored oxygen consumption rate and reduced total reactive oxygen species production. Infusion of exogenous mitochondria-rich fraction from mesenchymal stromal cells (mitotherapy) reduced peritoneal bacterial load, improved lung mechanics and histology, and decreased the expression of interleukin-1β, keratinocyte chemoattractant, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in lung tissue, while increasing keratinocyte growth factor expression and survival rate in cecal ligation and puncture-induced sepsis. Mitotherapy also reduced kidney and liver injury, plasma creatinine levels, and messenger RNA expressions of interleukin-18 in kidney, interleukin-6, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in liver, while increasing nuclear factor erythroid 2-related factor-2 and superoxide dismutase-2 in kidney and interleukin-10 in liver.
Mitotherapy decreased lung, liver, and kidney injury and increased survival rate in cecal ligation and puncture-induced sepsis.
确定从间充质基质细胞中分离的富含线粒体的部分的全身给药是否会减轻实验性脓毒症中的肺、肾和肝损伤。
动物研究。
实验室研究。
60 只 C57BL/6 雄性小鼠。
盲肠结扎和穿刺诱导脓毒症；假手术动物用作对照。手术后 24 小时，盲肠结扎和穿刺以及 Sham 动物进一步随机接受生理盐水或间充质基质细胞分离的富含线粒体的部分（3×106）IV。48 小时后，分析存活率、腹膜细菌负荷、肺、肾和肝损伤。此外，还评估了线粒体对肺上皮和内皮细胞耗氧率和活性氧产生的影响。
体外暴露于盲肠结扎和穿刺动物的肺上皮和内皮细胞中的富含线粒体的部分从间充质基质细胞中分离出来，恢复了耗氧率并减少了总活性氧的产生。外源性间充质基质细胞分离的富含线粒体的部分（线粒体治疗）的输注降低了腹膜细菌负荷，改善了肺力学和组织学，并降低了肺组织中白细胞介素-1β、角质形成细胞趋化因子、吲哚胺 2,3-双加氧酶-2 和程序性细胞死亡蛋白 1 的表达，同时增加了盲肠结扎和穿刺诱导的脓毒症中的角质形成细胞生长因子的表达和存活率。线粒体治疗还减少了肾和肝损伤、血浆肌酐水平以及肾中白细胞介素-18、白细胞介素-6、吲哚胺 2,3-双加氧酶-2 和程序性细胞死亡蛋白 1 的信使 RNA 表达，同时增加了核因子红细胞相关因子-2 和超氧化物歧化酶-2 在肾脏中的表达，以及肝脏中的白细胞介素-10。
线粒体治疗减少了盲肠结扎和穿刺诱导的脓毒症中的肺、肝和肾损伤，并提高了存活率。
