FOXO4通过调控细胞衰老在放射性肺纤维化中的作用和机制研究

Radiation-induced pulmonary fibrosis (RILF) is one of the serious complications of thoracic radiotherapy for thoracic tumors. There are few effective treatments for RILF in clinic. The pathogenesis of RILF has not been fully elucidated. It has been demonstrated that cell senescence contributes to the pathogenesis of RILF, and FOXO4 promotes cell senescence by interacting with p53. However, the role of FOXO4 in RILF is still unclear. In pre-experiments, we established a RILF mouse model, and found that FOXO4 and p21 were highly expressed in the lung tissues of the model mice. At the cellular level, inhibiting FOXO4 expression in irradiated type II alveolar epithelial cells eliminated senescent cells. And the fibrosis degree in RILF model mice was reduced by using a FOXO4 peptide (FOXO4-DRI) to interfere with the binding of FOXO4 and p53. Therefore, we hypothesized that FOXO4 could promote RILF by regulating cell senescence, and targeting FOXO4-p53 interaction could clear senescent cells and reverse RILF process. Based on the results of pre-experiments, we will further study how FOXO4 promotes RILF by regulating cell senescence, and verify the feasibility of targeting FOXO4 to reverse RILF, which may provide a novel target for RILF treatment.

放射性肺纤维化（RILF）是胸部肿瘤放射治疗的严重并发症之一，临床上缺乏有效的治疗方法。其发病机制尚未完全阐明，研究表明细胞衰老促进了RILF发生，叉头框O4蛋白（FOXO4）与p53结合促进细胞衰老的发生，但FOXO4在RILF中的作用尚不清楚。我们预实验发现RILF模型小鼠肺组织中高表达FOXO4和p21分子；抑制受照Ⅱ型肺泡上皮细胞FOXO4表达可清除衰老细胞；模型小鼠应用一种靶向干扰FOXO4与p53结合的多肽FOXO4-DRI后，肺纤维化程度减轻。因此，我们提出如下假设“FOXO4通过调控细胞衰老促进了RILF发生；靶向干扰FOXO4-p53的相互作用能够清除肺组织中的衰老细胞，逆转RILF进程”。在预实验基础上，本项目将研究FOXO4如何通过调控细胞衰老促进RILF发生，验证靶向FOXO4逆转RILF的可行性，为RILF治疗提供新靶点。

放射性肺纤维化（RILF）是胸部肿瘤放射治疗的严重并发症之一，临床上缺乏有效的治疗方法。其发病机制尚未完全阐明，研究表明细胞衰老促进了RILF发生，叉头框O4蛋白（FOXO4）与p53结合促进细胞衰老的发生，但FOXO4在RILF中的作用尚不清楚。我们的研究发现临床RILF患者和RILF模型小鼠肺组织中均高表达FOXO4和衰老相关分子；抑制受照Ⅱ型肺泡上皮细胞FOXO4的表达可清除衰老细胞；模型小鼠应用一种靶向干扰FOXO4与p53结合的多肽FOXO4-DRI后，抑制了衰老相关的p53-p21-p16信号通路的表达，肺组织中衰老细胞减少，肺纤维化程度减轻。研究结果提示FOXO4通过调控细胞衰老促进了RILF发生，靶向干扰FOXO4-p53的相互作用能够清除肺组织中的衰老细胞，逆转RILF进程。另外，博来霉素诱导的肺纤维化与放射性肺纤维化在在病理表现和发病机制上存在一定相似性，我们建立了博来霉素诱导的肺纤维化小鼠模型，并发现FOXO4-DRI也能够逆转博来霉素诱导的肺纤维化。FOXO4通过调控ECM受体相互作用信号通路，清除肌成纤维细胞，逆转博来霉素诱导的肺纤维化。