脂肪干细胞治疗放射性肺损伤及其机制研究

The present study is designed to observe the healing action of adipose-derived stem cells (ADSCs) on radiation-induced lung injury, further attempt to reveal the potential mechanisms in the cellular and molecular levels. ADSCs, which belong to mesenchymal stem cells, can differentiate into a variety of functional cells and show great promise in the field of regenerative medicine. Radiation-induced lung injury occurs as a result of exposure to ionizing radiation. Generally, such damage is divided into early inflammatory damage and later lung fibrosis. Reactive oxygen species generated by ionizing radiation initiate a cascade of inflammatory signaling, cause lung tissue damage and poor circulation, culminate in irreversible fibrosis. In this study, ADSCs are going to be isolated and intravenously administrated into mice models of radiation-induced lung injury. We will examine the suppressive effects of ADSCs on radiation-induce lung inflammation, oxidative stress, apoptosis and fibrosis. The relationship between the therapeutic effects and the versatility of ADSCs, including multilineage differentiation, anti-inflammation, anti-oxidative stress and angiogenesis promotion, will be also investigated, which may provide novel clues for the better treatment of radiation-induced lung injury.

本课题拟用脂肪干细胞来治疗放射性肺损伤，并在细胞分子水平上阐明其内在机制。脂肪干细胞属于间充质干细胞的一种，能分化为多种功能性细胞，在组织损伤治疗中有着广泛的应用前景。放射性肺损伤是电离辐射导致的肺组织初期炎症反应和晚期纤维化。电离辐射导致大量自由基在肺组织中产生，之后产生链级的炎症反应，导致肺组织损伤，血液循环不良，最终使肺组织不可逆的纤维化。本课题拟用脂肪干细胞处理小鼠放射性肺损伤模型，观察其对放射性肺损伤中的炎症反应、氧化应激反应、细胞凋亡、纤维化变的抑制作用，并进一步从脂肪干细胞的多向分化能力、抗炎能力、抗氧化应激能力，促进新生血管再生能力出发来探讨治疗的内在机制，为防治放射性肺损伤提供新的依据。

放射性肺损伤是由电离辐射引起的肺部早期炎症反应和晚期的慢性纤维化病变，是胸部肿瘤放疗中常见的并发症，本项目在小鼠放射性肺损伤模型中采用脂肪干细胞移植来观察其治疗效果，结果发现脂肪干细胞移植对小鼠放射性肺损伤有明显的治疗效果，可以减轻电离辐射引起的肺组织的早期炎症和晚期纤维化，其内在机制可能与促进肺干细胞修复损伤的肺组织有关。此外我们发现了凝胶溶蛋白的水平在放射性肺损伤早期就会发生明显的变化，采用凝胶溶蛋白抗体能够显著增强电离辐射对肺组织的损伤作用，提示提高凝胶溶蛋白的水平可能对放射性肺损伤有防治效果。在放射性肺损伤的炎症反应中我们研究了STAT3信号通路所起的作用，结果显示用STAT3通路在小鼠放射性肺损伤模型中明显激活，采用STAT3通路抑制剂处理可以抑制STAT3分子的磷酸化，减轻肺组织的炎症反应，维持肺部毛细血管的正常通透性，缓解肺组织的纤维化，提示抑制STAT3炎症通路可能是一种有效的防治放射性肺损伤的方法。本项目的成果揭示了放射性肺损伤中发生发展中的几个关键性事件，并通过调控这些靶点取得了防治放射性肺损伤的实验证据，为进一步探讨发现防治放射性肺损伤的有效方法提供了实验依据。