Department of Experimental Pharmacology and Toxicology, Pharmaceutical Science of Jilin University, Changchun, Jilin, 130021, China.
Department of Vascular Surgery, The first Hospital of Jilin University, Changchun, Jilin, 130021, China.
Sci Rep. 2019 Apr 3;9(1):5589. doi: 10.1038/s41598-019-41576-5.
The present study attempts to identify the optimal time duration for the administration of Ad-MSCs, in order to maximize its therapeutic benefits, and compare the degree of fibrosis among three different administration time points using the RILF rat model system. Ad-MSCs were delivered to Sprague-Dawley rats through the tail vein at the following different time points after thorax irradiation: two hours, seven days, and two hours + seven days. Post Ad-MSCs transplantation and the histopathological analysis of the lungs were performed along with analysis of inflammatory cytokine levels, including interleukin (IL)-1, IL-2, IL-6, IL-10 and tumor necrosis factor-α (TNF-α). In particular, pro-fibrotic factors (TGF-β1 and α-SMA) were also evaluated in serum and lung tissues. In addition, it was also determined whether Ad-MSCs had any role in inhibiting the transition of type II alveolar epithelial cells into fibroblasts in the lungs of injured rats. The present results demonstrated that the intravenous delivery of Ad-MSCs twice at the 2-hour and 7-day (R + MSC group) was effective in reducing lung fibrosis for long term durations, when compared with single delivery either at the two-hour or 7-day time points. In addition, a marked anti-inflammatory effect was also observed in RILF rats in the R + MSC group, as indicated by the reduced serum levels of pro-inflammatory cytokines (TNF-α, IL-1 and IL-6) and increased levels of anti-inflammatory cytokines IL-10 and IL-2. Rats that were delivered twice with Ad-MSCs (R + MSC group) exhibited significantly reduced TGF-β1 and α-SMA levels, in contrast to rats in the R + MSC or R + MSC groups, after four weeks. Furthermore, it was also noted that after four weeks, Ad-MSCs increased the number of lung epithelial cells (SP-C) and inhibited the lung fibroblastic cells (α-SMA) of rats in the R + MSC and R + MSC groups. The present study concluded that two injections of Ad-MSCs (R + MSC group) appear to be optimal for therapeutic efficacy and safety during RILF.
本研究旨在确定间充质干细胞（Ad-MSCs）治疗的最佳给药时间，以最大限度地提高其治疗效果，并通过 RILF 大鼠模型系统比较三种不同给药时间点的纤维化程度。将 Ad-MSCs 通过尾静脉递送至胸部照射后的 Sprague-Dawley 大鼠，给药时间点分别为：照射后 2 小时、7 天和 2 小时+7 天。在 Ad-MSCs 移植后，对肺部进行组织病理学分析，并检测炎症细胞因子水平，包括白细胞介素（IL）-1、IL-2、IL-6、IL-10 和肿瘤坏死因子-α（TNF-α）。此外，还评估了血清和肺组织中的促纤维化因子（TGF-β1 和 α-SMA）。另外，还确定了 Ad-MSCs 是否在抑制损伤大鼠肺部 II 型肺泡上皮细胞向成纤维细胞的转化方面发挥作用。本研究结果表明，与单次给药（2 小时或 7 天）相比，两次（2 小时和 7 天）静脉注射 Ad-MSCs（R+MSC 组）可有效减轻长期肺纤维化。此外，在 RILF 大鼠中还观察到明显的抗炎作用，表现为促炎细胞因子（TNF-α、IL-1 和 IL-6）血清水平降低，抗炎细胞因子 IL-10 和 IL-2 水平升高。与 R+MSC 组或 R+MSC 组相比，两次给予 Ad-MSCs（R+MSC 组）的大鼠在四周后 TGF-β1 和 α-SMA 水平显著降低。此外，还注意到，四周后，Ad-MSCs 增加了 R+MSC 组和 R+MSC 组大鼠的肺上皮细胞（SP-C）数量，并抑制了肺成纤维细胞（α-SMA）。本研究得出结论，两次注射 Ad-MSCs（R+MSC 组）在 RILF 中似乎具有最佳的治疗效果和安全性。
