Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Skin Res Technol. 2023 Jun;29(6):e13337. doi: 10.1111/srt.13337.
Radiation-induced skin injury, which may progress to fibrosis, is a severe side effect of radiotherapy in patients with cancer. However, currently, there is a lack of preventive or curative treatments for this injury. Meanwhile, the mechanisms underlying this injury remain poorly understood. Here, we elucidated whether autophagy is essential for the development of radiation-induced skin injury and the potential molecular pathways and mechanisms involved.
We used the myofibroblast-specific Atg7 knockout (namely, conditional Atg7 knockout) mice irradiated with a single electron beam irradiation dose of 30 Gy. Vaseline-based 0.2% rapamycin ointment was topically applied once daily from the day of irradiation for 30 days. On day 30 post irradiation, skin tissues were harvested for further analysis. In vitro, human foreskin fibroblast cells were treated with rapamycin (100 nM) for 24 h and pretreated with 3-MA (5 mM) for 12 h. Macroscopic skin manifestations, histological changes, and fibrosis markers at the mRNA and protein expression levels were measured. Post irradiation, the myofibroblast-specific autophagy-deficient (Atg7 Cre ) mice had increased fibrosis marker (COL1A1, CTGF, TGF-β1, and α-SMA) levels in the irradiated area and had more severe macroscopic skin manifestations than the control group (Atg7 Cre ) mice. Treatment with an autophagy agonist rapamycin attenuated macroscopic skin injury scores and skin fibrosis marker levels with decreased epidermal thickness and dermal collagen deposition in Atg7 Cre mice compared with the vehicle control. Moreover, in vitro experiment results were consistent with the in vivo results. Together with studies at the molecular level, we found that these changes involved the Akt/mTOR pathway. In addition, this phenomenon might also relate to Nrf2-autophagy signaling pathway under oxidative stress conditions.
In conclusion, Atg7 and autophagy-related mechanisms confer radioprotection, and reactivation of the autophagy process can be a novel therapeutic strategy to reduce and prevent the occurrence of radiodermatitis, particularly skin fibrosis, in patients with cancer.
放射诱导的皮肤损伤，可能进展为纤维化，是癌症患者放疗的一种严重副作用。然而，目前对此种损伤尚无预防或治疗方法。同时，这种损伤的潜在分子途径和机制也知之甚少。在这里，我们阐明了自噬是否对放射诱导的皮肤损伤的发生至关重要，以及涉及的潜在分子途径和机制。
我们使用肌成纤维细胞特异性 Atg7 敲除（即条件性 Atg7 敲除）小鼠，并用单电子束照射 30Gy。从照射之日起，每天用凡士林为基质的 0.2%雷帕霉素软膏局部涂抹一次，共 30 天。照射后 30 天，采集皮肤组织进行进一步分析。在体外，用雷帕霉素（100nM）处理人包皮成纤维细胞 24 小时，并预先用 3-MA（5mM）处理 12 小时。测量照射后纤维化标志物在 mRNA 和蛋白表达水平的变化。照射后，肌成纤维细胞特异性自噬缺陷（Atg7 Cre ）小鼠在照射区域的纤维化标志物（COL1A1、CTGF、TGF-β1 和α-SMA）水平升高，且宏观皮肤表现较对照组（Atg7 Cre ）小鼠更严重。与载体对照组相比，自噬激动剂雷帕霉素治疗可减轻 Atg7 Cre 小鼠的宏观皮肤损伤评分和皮肤纤维化标志物水平，降低表皮厚度和真皮胶原沉积。此外，体外实验结果与体内结果一致。结合分子水平的研究，我们发现这些变化涉及 Akt/mTOR 通路。此外，这种现象可能与氧化应激条件下 Nrf2-自噬信号通路有关。
总之，Atg7 和自噬相关机制提供放射保护，并且自噬过程的再激活可能成为减少和预防癌症患者放射性皮炎，特别是皮肤纤维化发生的一种新的治疗策略。
