Zhao Xinyao, Du Lehui, Ma Na, Tan Xin, Lei Xiao, Zhang Pei, Qu Baolin
Department of Radiation Oncology, Shijingshan Teaching Hospital of Capital Medical University, Shijingshan Hospital, Beijing, China.
Department of Radiation Oncology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
J Cancer Res Clin Oncol. 2025 Jan 25;151(2):48. doi: 10.1007/s00432-025-06088-y.
Radiation-induced lung injury (RILI) limits the efficacy of thoracic radiotherapy. However, the underlying mechanism of RILI remains unclear. cGAS-STING pathway is reported to be involved in the recognization of cytosolic dsDNA and various inflammatory diseases. This study aimed to investigate the role of cGAS-STING pathway in the development of RILI.
A pre-clinical mouse model of RILI was established by whole thorax irradiation and confirmed using H&E and Masson's trichrome staining. STING agonist (DMXAA) and antagonist(C-176) were administrated to modulate cGAS-STING pathway in vivo. Western blot and ELISA were used to determine the expression levels of different proteins.
Quantitation analysis showed dsDNA accumulation in lung tissue and western blot showed the up-regulation of cGAS and STING protein level post-irradiation, indicating pathway activation. Histological evaluation showed that C-176 administration ameliorated radiation-induced pulmonary inflammation and fibrosis, while DMXAA exhibited contrary effects. In further in vitro study, the release of dsDNA induced by radiation led to the activation of cGAS-STING pathway in RAW 264.7 cells, resulting in the polarization into M1 phenotype and pro-inflammatory production.
In summary, our data demonstrated a link between cGAS-STING pathway and the development of RILI, indicating its potential application in clinic.
放射性肺损伤（RILI）限制了胸部放疗的疗效。然而，RILI的潜在机制仍不清楚。据报道，cGAS-STING通路参与细胞质双链DNA的识别以及各种炎症性疾病。本研究旨在探讨cGAS-STING通路在RILI发生发展中的作用。
通过全胸照射建立RILI的临床前小鼠模型，并使用苏木精-伊红（H&E）染色和马松三色染色进行确认。给予STING激动剂（DMXAA）和拮抗剂（C-176）以在体内调节cGAS-STING通路。采用蛋白质免疫印迹法（Western blot）和酶联免疫吸附测定（ELISA）来测定不同蛋白质的表达水平。
定量分析显示肺组织中双链DNA积累，蛋白质免疫印迹法显示照射后cGAS和STING蛋白水平上调，表明该通路被激活。组织学评估显示，给予C-176可减轻放射性肺炎和肺纤维化，而DMXAA则表现出相反的作用。在进一步的体外研究中，辐射诱导的双链DNA释放导致RAW 264.7细胞中cGAS-STING通路激活，使其极化为M1表型并产生促炎因子。
总之，我们的数据证明了cGAS-STING通路与RILI发生发展之间的联系，表明其在临床上的潜在应用价值。
