Inhibition of Radiation-Induced Ccl2 Signaling Protects Lungs from Vascular Dysfunction and Endothelial Cell Loss.
Antioxid Redox Signal
; 30(2): 213-231, 2019 01 10.
Article
en En
| MEDLINE
| ID: mdl-29463096
ABSTRACT
Aims:
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.Results:
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 ex vivo cultured human normal lung tissue. Innovation 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.Conclusions:
Radioprotection of the normal tissue via 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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Endotelio Vascular
/
Transducción de Señal
/
Quimiocina CCL2
/
Células Endoteliales
/
Pulmón
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Idioma:
En
Revista:
Antioxid Redox Signal
Asunto de la revista:
METABOLISMO
Año:
2019
Tipo del documento:
Article
País de afiliación:
Alemania