低氧培养的间充质干细胞对放射性肺损伤的治疗效应及MIP-1β在该效应中的作用和机制研究

Radiation-induced lung injury (RILI) is a common complication of nuclear accident and thoracic radiotherapy with high mortality. The treatment for RILI remains a difficult issue with less effective therapies. Recently, the study of mesenchymal stem cells (MSC) provides novel therapeutic strategies for RILI. However, the local ischemia and hypoxia condition and the highly oxidative stress condition of radiated lung tissue greatly decrease the survival time of exogenous MSC in damaged lung tissues, which subsequently limited the treatment effect of MSC for RILI. Therefore, we cultured MSC under hypoxia condition so that MSC acquired the tolerance to hypoxia. As a result, hypoxia could promote the proliferation of MSCs and improve their therapeutic effect on RILI. Protein microarray technique further selected the MIP-1β as a crucial regulator. Based on the above results, we apply for this project in purposes of: (1) determining the exact effect of hypoxia-cultured MSCs on RILI, (2) interpreting the role of MIP-1β in MSCs’ therapeutic effect, (3) finding the upstream transcription factor of MIP-1β under hypoxia condition, and investigating the involved mechanism that MIP-1β act on radiated cells. We aim to provide a new way to improve the therapeutic effect of MSCs on RILI and throw light upon the specific mechanisms.

放射性肺损伤（RILI）是核事故及胸部肿瘤放疗中的常见并发症，死亡率高，救治难度大，尚缺乏有效的治疗手段。近年来，间充质干细胞（MSC）的研究为该病的治疗提供了新的方向。但由于辐射导致的肺组织局部缺血缺氧和高氧化应激，使得外源性MSC在肺组织存活时间减少，限制了其对RILI的疗效。为此，我们予以MSC进行低氧预处理以期提高其对低氧环境的耐受性，结果发现低氧能改变MSC的增殖特性，提高了其对RILI的治疗作用。进一步，我们运用抗体芯片技术，筛选出MIP-1β作为影响低氧MSC治疗RILI能力的关键分子。本项目根据以上研究为基础，拟开展研究：1、系统研究低氧预处理培养的MSC对RILI的治疗效果；2、明确MIP-1β是否是介导该效应的关键分子；3、对MIP-1β上游调控和下游作用的具体机制进行详细的探讨。通过以上研究，希望为增强MSCs对RILI的疗效提供新思路，为其中的具体机制予以详细阐明。

放射性肺损伤一直是放射医学领域研究的重点和难点，其发生机制复杂，涉及的环节众多，尚无理想的防治手段。间充质干细胞研究的开展为放射性肺损伤的防治提供了新的方向，但受制于照射所导致的肺组织缺血缺氧和高氧化应激的环境，使得外源性的BMSCs在受照肺组织存活时间减少，降低了其对RILI的治疗效果。本项目的实验结果，从动物、细胞等多个层面系统的研究了低氧培养的BMSCs对RILI的治疗作用，不仅考察了其治疗的总体效应，更从RILI发生的不同阶段（早期放射性肺炎和晚期放射性肺纤维化），多个层次（动物组织、细胞水平）进一步明确了该治疗效应的作用强度。通过进一步的研究，阐明了低氧BMSCs治疗RILI的作用分子机制，即低氧通过上调SP7后促进MIP-1β转录，而分泌的MIP-1β又进一步激活CCR5从而实现减轻肺损伤的作用。本项目为MSCs防治放射性肺损伤的研究提供了新的思路，为筛选增强MSCs疗效的关键分子提供了参考依据。