Inhibition of Radiation-Induced Ccl2 Signaling Protects Lungs from Vascular Dysfunction and Endothelial Cell Loss

Antioxidants & Redox Signaling
Alina WiesemannDiana Klein

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 ...Continue Reading

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Citations

Aug 25, 2020·Stem Cells Translational Medicine·Jennifer SteensDiana Klein
May 10, 2020·International Journal of Molecular Sciences·Christine HanselDiana Klein
Apr 27, 2019·Frontiers in Immunology·Simone de LeveVerena Jendrossek
Oct 19, 2019·Cancers·Simone de LeveVerena Jendrossek
Nov 13, 2019·Cellular and Molecular Life Sciences : CMLS·Jennifer SteensDiana Klein
Nov 17, 2020·Experimental and Molecular Pathology·Qi GuoLei Liu
Nov 14, 2020·International Journal of Molecular Sciences·Jan KorbeckiIrena Baranowska-Bosiacka
Jun 4, 2021·Frontiers in Immunology·Julie ConstanzoJean-Pierre Pouget
Jul 3, 2021·International Journal of Molecular Sciences·Christine HanselDiana Klein
Dec 21, 2021·Frontiers in Immunology·Zengfu ZhangDawei Chen
Jan 9, 2022·Journal of Cachexia, Sarcopenia and Muscle·Jacob G KallenbachJoe V Chakkalakal

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Methods Mentioned

BETA
flow cytometry
electron microscopy
FACS
light microscopy
fluorescent
activated cell sorting
fluorescence microscopy

Software Mentioned

Prism
GraphPad
FACS DIVA
Focinator

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