Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Cell Transplant. 2013;22(9):1667-81. doi: 10.3727/096368912X657765. Epub 2012 Oct 8.
Acute paraquat (PQ) poisoning induces redox cycle and leads to fatal injury of lung. Clinical management is supportive in nature due to lack of effective antidote, and the mortality is very high. Mesenchymal stem cells (MSCs) process the properties of immunomodulation, anti-inflammatory, and antifibrotic effects and oxidative stress resistance. MSC transplantation may theoretically serve as an antidote in PQ intoxication. In this study, we examined the potential therapeutic effects of MSCs in PQ-induced lung injury. The degree of PQ toxicity in the rat type II pneumocyte cell line, L2, and MSCs was evaluated by examining cell viability, ultrastructural changes, and gene expression. L2 cells treated with 0.5 mM PQ were cocultured in the absence or presence of MSCs. For the in vivo study, adult male SD rats were administered an intraperitoneal injection of PQ (24 mg/kg body weight) and were divided into three groups: group I, control; group II, cyclophosphamide and methylprednisolone; group III, MSC transplantation 6 h after PQ exposure. MSCs were relatively resistant to PQ toxicity. Coculture with MSCs significantly inhibited PQ accumulation in L2 cells and upregulated the expression of antioxidative heme oxygenase 1 and metallothionein 1a genes, reversed epithelial-to-mesenchymal transition, and increased the viability of PQ-exposed L2 cells. Treatment with MSCs resulted in a significant reduction in severity of liver and renal function deterioration, alleviated lung injury, and prolonged the life span of rats. Altogether, our results suggest that MSCs possess antidote-like effect through multifactorial protection mechanism. The results of this preclinical study demonstrate that transplantation of MSCs may be a promising therapy and should be further validated clinically.
急性百草枯（PQ）中毒可诱导氧化还原循环，导致致命的肺损伤。由于缺乏有效的解毒剂，临床治疗主要是支持性的，死亡率非常高。间充质干细胞（MSCs）具有免疫调节、抗炎、抗纤维化和抗氧化应激的特性。MSCs 移植理论上可作为 PQ 中毒的解毒剂。在这项研究中，我们研究了 MSCs 在 PQ 诱导的肺损伤中的潜在治疗作用。通过检测细胞活力、超微结构变化和基因表达，评估了 PQ 对大鼠 II 型肺泡细胞系 L2 和 MSCs 的毒性程度。用 0.5mM PQ 处理 L2 细胞，并在有无 MSCs 的情况下进行共培养。在体内研究中，成年雄性 SD 大鼠腹腔注射 PQ（24mg/kg 体重），并分为三组：I 组，对照组；II 组，环磷酰胺和甲基强的松龙；III 组，PQ 暴露后 6 小时进行 MSC 移植。MSCs 对 PQ 毒性相对耐受。与 MSCs 共培养可显著抑制 PQ 在 L2 细胞中的积累，上调抗氧化血红素加氧酶 1 和金属硫蛋白 1a 基因的表达，逆转上皮间质转化，提高 PQ 暴露的 L2 细胞活力。MSCs 治疗可显著降低肝肾功能恶化的严重程度，减轻肺损伤，延长大鼠的寿命。总之，我们的结果表明，MSCs 通过多因素保护机制具有解毒剂样作用。这项临床前研究的结果表明，MSCs 移植可能是一种有前途的治疗方法，应进一步临床验证。
