二十碳五烯酸增强脂肪组织来源的间充质基质细胞对实验性脓毒症肺和远隔器官损伤的治疗作用。

Eicosapentaenoic acid potentiates the therapeutic effects of adipose tissue-derived mesenchymal stromal cells on lung and distal organ injury in experimental sepsis.

机构信息

Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, s/n, Bloco G-014, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil.

National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.

出版信息

Stem Cell Res Ther. 2019 Aug 23;10(1):264. doi: 10.1186/s13287-019-1365-z.

DOI:10.1186/s13287-019-1365-z

PMID:31443678

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6708232/

Abstract

BACKGROUND

Even though mesenchymal stromal cells (MSCs) mitigate lung and distal organ damage in experimental polymicrobial sepsis, mortality remains high. We investigated whether preconditioning with eicosapentaenoic acid (EPA) would potentiate MSC actions in experimental sepsis by further decreasing lung and distal organ injury, thereby improving survival.

METHODS

In C57BL/6 mice, sepsis was induced by cecal hligation and puncture (CLP); sham-operated animals were used as control. Twenty-four hours after surgery, CLP mice were further randomized to receive saline, adipose tissue-derived (AD)-MSCs (10, nonpreconditioned), or AD-MSCs preconditioned with EPA for 6 h (10, EPA-preconditioned MSCs) intravenously. After 24 h, survival rate, sepsis severity score, lung mechanics and histology, protein level of selected biomarkers in lung tissue, cellularity in blood, distal organ damage, and MSC distribution (by technetium-99m tagging) were analyzed. Additionally, the effects of EPA on the secretion of resolvin-D (RvD), prostaglandin E (PGE), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated in vitro.

RESULTS

Nonpreconditioned and EPA-preconditioned AD-MSCs exhibited similar viability and differentiation capacity, accumulated mainly in the lungs and kidneys following systemic administration. Compared to nonpreconditioned AD-MSCs, EPA-preconditioned AD-MSCs further reduced static lung elastance, alveolar collapse, interstitial edema, alveolar septal inflammation, collagen fiber content, neutrophil cell count as well as protein levels of interleukin-1β and keratinocyte chemoattractant in lung tissue, and morphological abnormalities in the heart (cardiac myocyte architecture), liver (hepatocyte disarrangement and Kupffer cell hyperplasia), kidney (acute tubular necrosis), spleen (increased number of megakaryocytes and lymphocytes), and small bowel (villi architecture disorganization). EPA preconditioning of MSCs resulted in increased secretion of pro-resolution and anti-inflammatory mediators (RvD, PGE, IL-10, and TGF-β).

CONCLUSIONS

Compared to nonpreconditioned cells, EPA-preconditioned AD-MSCs yielded further reductions in the lung and distal organ injury, resulting in greater improvement in sepsis severity score and higher survival rate in CLP-induced experimental sepsis. This may be a promising therapeutic approach to improve outcome in septic patients.

摘要

背景

间充质基质细胞（MSCs）可减轻实验性多微生物脓毒症中的肺和远端器官损伤，但死亡率仍然很高。我们研究了预先用二十碳五烯酸（EPA）处理是否会通过进一步减少肺和远端器官损伤来增强 MSC 在实验性脓毒症中的作用，从而提高存活率。

方法

在 C57BL/6 小鼠中，通过盲肠结扎和穿刺（CLP）诱导脓毒症；假手术动物用作对照。手术后 24 小时，CLP 小鼠进一步随机接受盐水、脂肪组织衍生（AD）-MSC（10，未预处理）或 EPA 预处理 6 小时的 AD-MSC（10，EPA 预处理 MSC）静脉内注射。24 小时后，分析存活率、脓毒症严重程度评分、肺力学和组织学、肺组织中选定生物标志物的蛋白水平、血液中的细胞数、远端器官损伤以及 MSC 分布（通过锝-99m 标记）。此外，还在体外评估了 EPA 对 MSC 分泌分辨率分解产物（RvD）、前列腺素 E（PGE）、白细胞介素（IL）-10 和转化生长因子（TGF）-β1 的影响。

结果

非预处理和 EPA 预处理的 AD-MSC 表现出相似的活力和分化能力，在全身给药后主要积聚在肺和肾脏中。与非预处理的 AD-MSC 相比，EPA 预处理的 AD-MSC 进一步降低了静态肺弹性、肺泡塌陷、间质水肿、肺泡隔炎症、胶原纤维含量、肺组织中白细胞介素-1β 和角质形成细胞趋化因子的蛋白水平，以及心脏（心肌细胞结构）、肝脏（肝细胞排列紊乱和库普弗细胞增生）、肾脏（急性肾小管坏死）、脾脏（巨核细胞和淋巴细胞数量增加）和小肠（绒毛结构紊乱）的形态异常。MSC 的 EPA 预处理导致促分辨率和抗炎介质（RvD、PGE、IL-10 和 TGF-β）的分泌增加。