Zhao Yaqin, Wei Yuanfeng, Hou Wanting, Huang Xianzhou, Li Qiaoqi, Yi Cheng
Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Front Immunol. 2025 Jul 31;16:1600776. doi: 10.3389/fimmu.2025.1600776. eCollection 2025.
Radiation-induced pulmonary fibrosis (RIPF) is a chronic, fatal and irreversible disease that develops after a consequence of thoracic radiation therapy and few effective treatments have been developed for this condition. Repeated inflammation and excessive accumulation of fibroblasts are features of RIPF. Thus, reducing inflammation and inducing lung fibroblast apoptosis may be an effective strategy for RIPF. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as a natural immunomodulator, can specifically bind to death receptors (DRs) and selectively induce apoptosis in many cells. In our research, we have constructed a novel TRAIL mutant with CPP-like and Smac-like structure (R5S4TRAIL) and aim to explore the role and molecular mechanism of R5S4TRAIL in RIPF.
Firstly, the RIPF model was established in C57BL/6 mice. Then, the mice were treated with saline (Con group), dexamethasone (Dex group), or R5S4TRAIL (RST group). The remission of RIPF was evaluated by micro-CT, Masson and hematoxylin-eosin (HE) staining. Next, the molecular mechanisms of R5S4TRAIL in RIPF were explored and vitro.
We successfully established the RIPF model and found that R5S4TRAIL treatment could regulate the expression of inflammatory-related cytokines and attenuate the inflammatory response. Meanwhile, R5S4TRAIL treatment could upregulate DR5 expression and induce apoptosis in lung fibroblasts. Briefly, treatment with R5S4TRAIL could alleviate RIPF.
R5S4TRAIL has the potential to ameliorate RIPF by alleviating inflammatory responses and promoting apoptosis of fibroblasts.
放射性肺纤维化（RIPF）是一种慢性、致命且不可逆的疾病，它是胸部放射治疗的后果，目前针对这种疾病几乎没有开发出有效的治疗方法。反复炎症和成纤维细胞过度积累是RIPF的特征。因此，减轻炎症并诱导肺成纤维细胞凋亡可能是治疗RIPF的有效策略。肿瘤坏死因子相关凋亡诱导配体（TRAIL）作为一种天然免疫调节剂，可特异性结合死亡受体（DRs）并在许多细胞中选择性诱导凋亡。在我们的研究中，我们构建了一种具有类CPP和类Smac结构的新型TRAIL突变体（R5S4TRAIL），旨在探讨R5S4TRAIL在RIPF中的作用及分子机制。
首先，在C57BL/6小鼠中建立RIPF模型。然后，用生理盐水（Con组）、地塞米松（Dex组）或R5S4TRAIL（RST组）对小鼠进行治疗。通过微型计算机断层扫描（micro-CT）、Masson染色和苏木精-伊红（HE）染色评估RIPF的缓解情况。接下来，在体内和体外探索R5S4TRAIL在RIPF中的分子机制。
我们成功建立了RIPF模型，并发现R5S4TRAIL治疗可调节炎症相关细胞因子的表达并减轻炎症反应。同时，R5S4TRAIL治疗可上调DR5表达并诱导肺成纤维细胞凋亡。简而言之，R5S4TRAIL治疗可减轻RIPF。
R5S4TRAIL有潜力通过减轻炎症反应和促进成纤维细胞凋亡来改善RIPF。
