1 Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital , Essen, Germany .
2 Department of Thoracic Surgery and Surgical Endoscopy, Ruhrlandklinik-University Clinic Essen , Essen, Germany .
Antioxid Redox Signal. 2019 Jan 10;30(2):213-231. doi: 10.1089/ars.2017.7458. Epub 2018 Apr 2.
Radiation-induced normal tissue toxicity often precludes the application of curative radiation doses. Here we investigated the therapeutic potential of chemokine C-C motif ligand 2 (Ccl2) signaling inhibition to protect normal lung tissue from radiotherapy (RT)-induced injury. RT-induced vascular dysfunction and associated adverse effects can be efficiently antagonized by inhibition of Ccl2 signaling using either the selective Ccl2 inhibitor bindarit (BIN) or mice deficient for the main Ccl2 receptor CCR2 (KO). BIN-treatment efficiently counteracted the RT-induced expression of Ccl2, normalized endothelial cell (EC) morphology and vascular function, and limited lung inflammation and metastasis early after irradiation (acute effects). A similar protection of the vascular compartment was detected by loss of Ccl2 signaling in lungs of CCR2-KO mice. Long-term Ccl2 signaling inhibition also significantly limited EC loss and accompanied fibrosis progression as adverse late effect. With respect to the human situation, we further confirmed that Ccl2 secreted by RT-induced senescent epithelial cells resulted in the activation of normally quiescent but DNA-damaged EC finally leading to EC loss in cultured human normal lung tissue. Abrogation of certain aspects of the secretome of irradiated resident lung cells, in particular signaling inhibition of the senescence-associated secretory phenotype-factor Ccl2 secreted predominantly by RT-induced senescent epithelial cells, resulted in protection of the endothelial compartment. Radioprotection of the normal tissue Ccl2 signaling inhibition without simultaneous protection or preferable radiosensitization of tumor tissue might improve local tumor control and survival, because higher doses of radiation could be used.
辐射诱导的正常组织毒性常常使治疗性放射剂量的应用受到限制。在这里，我们研究了趋化因子 C-C 基序配体 2 (Ccl2) 信号抑制对保护正常肺组织免受放射治疗 (RT) 诱导损伤的治疗潜力。 RT 诱导的血管功能障碍和相关的不良反应可以通过抑制 Ccl2 信号来有效拮抗，方法是使用选择性 Ccl2 抑制剂 bindarit (BIN) 或缺乏主要 Ccl2 受体 CCR2 的小鼠 (KO)。 BIN 治疗可有效拮抗 RT 诱导的 Ccl2 表达，使内皮细胞 (EC) 形态和血管功能正常化，并限制照射后早期的肺部炎症和转移 (急性效应)。在 CCR2-KO 小鼠的肺部中，通过缺失 Ccl2 信号也检测到了对血管区室的类似保护。长期 Ccl2 信号抑制也显著限制了 EC 的丧失，并伴有纤维化的进展，作为不良的晚期效应。就人类情况而言，我们进一步证实 RT 诱导的衰老上皮细胞分泌的 Ccl2 导致正常静止但 DNA 受损的 EC 激活，最终导致培养的人正常肺组织中 EC 的丧失。 阻断照射的常驻肺细胞的某些分泌组部分，特别是 RT 诱导的衰老上皮细胞分泌的衰老相关分泌表型因子 Ccl2 的信号抑制，可保护血管区室。 在不同时保护或更好地放射敏化肿瘤组织的情况下，正常组织的 Ccl2 信号抑制可能会改善局部肿瘤控制和生存，因为可以使用更高剂量的辐射。
