PO-112 The senescence associated secretory phenotype (sasp)-factor ccl2 fosters vascular dysfunction and endothelial cell loss in radiation-induced lung disease

Introduction Blood vessels are critical targets of the radiation response. Acute vascular damage and dysfunction upon irradiation as well as delayed endothelial cell loss are particularly prominent in the radiation response of normal tissues. However, the mechanisms underlying radiation-induced adverse effects in the vascular compartment remain elusive and no causative radioprotective treatment is available to date. Material and methods Here we investigated the therapeutic potential of Ccl2 signalling inhibition to specifically protect endothelial cells (EC) from injury of radiation-induced acute and late toxicity in lungs after whole thorax irradiation (WTI) using a mouse model of radiation-induced pneumopathy as well as ex vivo cultured human lung tissue. Results and discussions RT-induced vascular dysfunction and associated adverse effects can be efficiently antagonised by inhibition of Ccl2 signalling 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, normalised 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 signalling in lungs of CCR2-KO mice. Long-term Ccl2 signalling 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 ex vivo cultured human normal lung tissue. Abrogation of certain aspects of the secretome of irradiated resident lung cells, in particular signalling inhibition of the senescence associated secretory phenotype (SASP)-factor Ccl2 secreted predominantly by RT-induced senescent epithelial cells resulted in protection of the endothelial compartment. Conclusion Radioprotection of the normal tissue via Ccl2 signalling inhibition without simultaneous protection or preferable radiosensitization of tumour tissue might improve local tumour control and survival, because higher doses of radiation could be used.