Radiation-induced lung injury (RILI) mainly contributes to the complications of thoracic radiotherapy. RILI can be divided into radiation pneumonia (RP) and radiation-induced lung fibrosis (RILF). Once RILF occurs, patients will eventually develop irreversible respiratory failure; thus, a new treatment strategy to prevent RILI is urgently needed. This study explored the therapeutic effect of pirfenidone (PFD), a Food and Drug Administration (FDA)-approved drug for (IPF) treatment, and its mechanism in the treatment of RILF. In vivo, C57BL/6 mice received a 50 Gy dose of X-ray radiation to the whole thorax with or without the administration of PFD. Collagen deposition and fibrosis in the lung were reversed by PFD treatment, which was associated with reduced M2 macrophage infiltration and inhibition of the transforming growth factor-β1 (TGF-β1)/Drosophila mothers against the decapentaplegic 3 (Smad3) signalling pathway. Moreover, PFD treatment decreased the radiation-induced expression of TGF-β1 and phosphorylation of Smad3 in alveolar epithelial cells (AECs) and vascular endothelial cells (VECs). Furthermore, IL-4–induced M2 macrophage polarization and IL-13–induced M2 macrophage polarization were suppressed by PFD treatment in vitro, resulting in reductions in the release of arginase-1 (ARG-1), chitinase 3-like 3 (YM-1) and TGF-β1. Notably, the PFD-induced inhibitory effects on M2 macrophage polarization were associated with downregulation of nuclear factor kappa-B (NF-κB) p50 activity. Additionally, PFD could significantly inhibit ionizing radiation-induced chemokine secretion in MLE-12 cells and consequently impair the migration of RAW264.7 cells. PFD could also eliminate TGF-β1 from M2 macrophages by attenuating the activation of TGF-β1/Smad3. In conclusion, PFD is a potential therapeutic agent to ameliorate fibrosis in RILF by reducing M2 macrophage infiltration and inhibiting the activation of TGF-β1/Smad3.

中文翻译：

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吡非尼酮通过抑制 TGF-β1/Smad3 通路调节巨噬细胞极化并改善辐射诱导的肺纤维化

放射性肺损伤（RILI）主要导致胸部放射治疗的并发症。RILI可分为放射性肺炎（RP）和放射性肺纤维化（RILF）。一旦发生RILF，患者最终会出现不可逆的呼吸衰竭；因此，迫切需要一种新的治疗策略来预防 RILI。本研究探讨了食品和药物管理局 (FDA) 批准的 (IPF) 治疗药物吡非尼酮 (PFD) 的治疗效果及其治疗 RILF 的机制。在体内，C57BL/6 小鼠在有或没有给予 PFD 的情况下对整个胸部接受 50 Gy 剂量的 X 射线辐射。PFD治疗逆转了肺中的胶原蛋白沉积和纤维化，这与减少 M2 巨噬细胞浸润和抑制转化生长因子-β1 (TGF-β1)/果蝇母体对 decapentaplegic 3 (Smad3) 信号通路有关。此外，PFD 治疗降低了肺泡上皮细胞 (AECs) 和血管内皮细胞 (VECs) 中辐射诱导的 TGF-β1 表达和 Smad3 磷酸化。此外，体外 PFD 处理抑制了 IL-4 诱导的 M2 巨噬细胞极化和 IL-13 诱导的 M2 巨噬细胞极化，导致精氨酸酶 1 (ARG-1)、几丁质酶 3 样 3 (YM -1) 和 TGF-β1。值得注意的是，PFD 诱导的对 M2 巨噬细胞极化的抑制作用与核因子 kappa-B (NF-κB) p50 活性的下调有关。此外，PFD可显着抑制MLE-12细胞中电离辐射诱导的趋化因子分泌，从而损害RAW264.7细胞的迁移。PFD 还可以通过减弱 TGF-β1/Smad3 的激活来消除 M2 巨噬细胞中的 TGF-β1。总之，PFD 是一种通过减少 M2 巨噬细胞浸润和抑制 TGF-β1/Smad3 活化来改善 RILF 纤维化的潜在治疗剂。