Wei Li, Zhang Jing, Yang Zai-Liang, You Hua
Key Laboratory of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing, China.
Oncology Department, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, China.
Cytotherapy. 2017 May;19(5):586-602. doi: 10.1016/j.jcyt.2017.02.359. Epub 2017 Mar 15.
Pulmonary fibrosis induced by irradiation is a significant problem of radiotherapy in cancer patients. Extracellular superoxide dismutase (SOD3) is found to be predominantly and highly expressed in the extracellular matrix of lung and plays a pivotal role against oxidative damage. Early administration of mesenchymal stromal cells (MSCs) has been demonstrated to reduce fibrosis of damaged lung. However, injection of MSCs at a later stage would be involved in fibrosis development. The present study aimed to determine whether injection of human umbilical cord-derived MSCs (UC-MSCs) over-expressing SOD3 at the established fibrosis stage would have beneficial effects in a mice model of radiation pulmonary fibrosis.
Herein, pulmonary fibrosis in mice was induced using Cobalt-60 (Co) irradiator with 20 Gy, followed by intravenous injection of UC-MSCs, transduced or not to express SOD3 at 2 h (early delivery) and 60 day (late delivery) post-irradiation, respectively.
Our results demonstrated that the early administration of UC-MSCs could attenuate the microscopic damage, reduce collagen deposition, inhibit (myo)fibroblast proliferation, reduce inflammatory cell infiltration, protect alveolar type II (AE2) cell injury, prevent oxidative stress and increase antioxidant status, and reduce pro-fibrotic cytokine level in serum. Furthermore, the early treatment with SOD3-infected UC-MSCs resulted in better improvement. However, we failed to observe the therapeutic effects of UC-MSCs, transduced to express SOD3, during established fibrosis.
Altogether, our results demonstrated that the early treatment with UC-MSCs alone significantly reduced radiation pulmonary fibrosis in mice through paracrine effects, with further improvement by administration of SOD3-infected UC-MSCs, suggesting that SOD3-infected UC-MSCs may be a potential cell-based gene therapy to treat clinical radiation pulmonary fibrosis.
放疗诱导的肺纤维化是癌症患者放疗中的一个重要问题。细胞外超氧化物歧化酶（SOD3）主要在肺的细胞外基质中高表达，对抵抗氧化损伤起关键作用。已证明早期给予间充质基质细胞（MSCs）可减轻受损肺的纤维化。然而，在后期注射MSCs会参与纤维化的发展。本研究旨在确定在已建立纤维化阶段注射过表达SOD3的人脐带间充质干细胞（UC-MSCs）对放射性肺纤维化小鼠模型是否有有益作用。
在此，用钴-60（Co）辐照器以20 Gy诱导小鼠肺纤维化，然后分别在照射后2小时（早期给药）和60天（晚期给药）静脉注射转导或未转导以表达SOD3的UC-MSCs。
我们的结果表明，早期给予UC-MSCs可减轻微观损伤、减少胶原蛋白沉积、抑制（肌）成纤维细胞增殖、减少炎性细胞浸润、保护II型肺泡（AE2）细胞损伤、预防氧化应激并提高抗氧化状态，以及降低血清中促纤维化细胞因子水平。此外，用SOD3感染的UC-MSCs进行早期治疗效果更佳。然而，在已建立纤维化期间，我们未观察到转导以表达SOD3的UC-MSCs的治疗效果。
总之，我们的结果表明，早期单独用UC-MSCs治疗可通过旁分泌作用显著减轻小鼠放射性肺纤维化，给予SOD3感染的UC-MSCs可进一步改善，这表明SOD3感染的UC-MSCs可能是一种潜在的基于细胞的基因疗法来治疗临床放射性肺纤维化。
