Background. Ischemia reperfusion injury (IRI) is the major cause of intestinal damage in clinic. Although either mesenchymal stromal cells (MSCs) or interleukin 37 (IL-37) shows some beneficial roles to ameliorate IRI, their effects are limited. In this study, the preventative effects of IL-37 gene-modified MSCs (IL-37-MSCs) on intestinal IRI are investigated. Methods. Intestinal IRI model was established by occluding the superior mesenteric artery for 30 minutes and then reperfused for 72 hours in rats. Forty adult male Sprague-Dawley rats were randomly divided into the sham control, IL-37-MSC-treated, MSC-treated, recombinant IL-37- (rIL-37-) treated, and untreated groups. Intestinal damage was assessed by H&E staining. The levels of gut barrier function factors (diamine oxidase and D-Lactate) and inflammation cytokine IL-1β were assayed using ELISA. The synthesis of tissue damage-related NLRP3 inflammasome and downstream cascade reactions including cleaved caspase-1, IL-1β, and IL-18 was detected by western blot. The mRNA levels of proinflammatory mediators IL-6 and TNF-α, which are downstream of IL-1β and IL-18, were determined by qPCR. Data were analyzed by one-way analysis of variance (ANOVA) after the normality test and followed by post hoc analysis with the least significant difference (LSD) test. Results. IL-37-MSCs were able to migrate to the damaged tissue and significantly inhibit intestinal IRI. As compared with MSCs or the rIL-37 monotherapy group, IL-37-MSC treatment both improved gut barrier function and decreased local and systemic inflammation cytokine IL-1β level in IRI rats. In addition, tissue damage-related NLRP3 and downstream targets (cleaved caspase-1, IL-1β, and IL-18) were significantly decreased in IRI rats treated with IL-37-MSCs. Furthermore, IL-1β- and IL-18-related proinflammatory mediator IL-6 and TNF-α mRNA expressions were all significantly decreased in IRI rats treated with IL-37-MSCs. Conclusion. The results suggest that IL-37 gene modification significantly enhances the protective effects of MSCs against intestinal IRI. In addition, NLRP3-related signaling pathways could be associated with IL-37-MSC-mediated protection.

中文翻译：

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IL-37基因修饰增强间充质基质细胞对肠缺血再灌注损伤的保护作用。

背景。缺血再灌注损伤（IRI）是临床上肠道损伤的主要原因。尽管间充质基质细胞 (MSCs) 或白细胞介素 37 (IL-37) 显示出一些改善 IRI 的有益作用，但它们的作用是有限的。在这项研究中，研究了 IL-37 基因修饰的 MSCs (IL-37-MSCs) 对肠道 IRI 的预防作用。方法. 大鼠肠系膜上动脉闭塞30分钟，再灌注72小时，建立肠IRI模型。将 40 只成年雄性 Sprague-Dawley 大鼠随机分为假对照组、IL-37-MSC 治疗组、MSC 治疗组、重组 IL-37- (rIL-37-) ​​治疗组和未治疗组。通过 H&E 染色评估肠损伤。使用ELISA测定肠道屏障功能因子（二胺氧化酶和D-乳酸）和炎症细胞因子IL-1β的水平。通过蛋白质印迹检测组织损伤相关 NLRP3 炎性体的合成和下游级联反应，包括裂解的 caspase-1、IL-1 β和 IL-18。IL-1 β下游的促炎介质 IL-6 和 TNF- α的 mRNA 水平和 IL-18，通过 qPCR 确定。在正态性检验后通过单因素方差分析 (ANOVA) 分析数据，然后通过最小显着性差异 (LSD) 检验进行事后分析。结果。IL-37-MSCs能够迁移到受损组织并显着抑制肠道IRI。与 MSCs 或 rIL-37 单药治疗组相比，IL-37-MSC 治疗既改善了 IRI 大鼠的肠道屏障功能，又降低了局部和全身炎症细胞因子 IL-1 β水平。此外，在用 IL-37-MSCs 治疗的 IRI 大鼠中，组织损伤相关的 NLRP3 和下游靶标（裂解的 caspase-1、IL-1 β和 IL-18）显着降低。此外，IL-1 β- 和 IL-18 相关的促炎介质 IL-6 和 TNF- α mRNA 表达在用 IL-37-MSCs 治疗的 IRI 大鼠中均显着降低。结论。结果表明IL-37基因修饰显着增强了MSCs对肠道IRI的保护作用。此外，NLRP3 相关的信号通路可能与 IL-37-MSC 介导的保护有关。