Inhibition of the CXCL12/CXCR4-axis as preventive therapy for radiation-induced pulmonary fibrosis.
BACKGROUND
A devastating late injury caused by radiation is pulmonary fibrosis. This risk may limit the volume of irradiation and compromise potentially curative therapy. Therefore, development of a therapy to prevent this toxicity can be of great benefit for this patient population. Activation of the chemokine receptor CXCR4 by its ligand stromal cell-derived factor 1 (SDF-1/CXCL12) may be important in the development of radiation-induced pulmonary fibrosis. Here, we tested whether MSX-122, a novel small molecule and partial CXCR4 antagonist, can block development of this fibrotic process.


RESULTS
The radiation-induced lung fibrosis model used was C57BL/6 mice irradiated to the entire thorax or right hemithorax to 20 Gy. Our parabiotic model involved joining a transgenic C57BL/6 mouse expressing GFP with a wild-type mouse that was subsequently irradiated to assess for migration of GFP+ bone marrow-derived progenitor cells to the irradiated lung. CXCL12 levels in the bronchoalveolar lavage fluid (BALF) and serum after irradiation were determined by ELISA. CXCR4 and CXCL12 mRNA in the irradiated lung was determined by RNase protection assay. Irradiated mice were treated daily with AMD3100, an established CXCR4 antagonist; MSX-122; and their corresponding vehicles to determine impact of drug treatment on fibrosis development. Fibrosis was assessed by serial CTs and histology. After irradiation, CXCL12 levels increased in BALF and serum with a corresponding rise in CXCR4 mRNA within irradiated lungs consistent with recruitment of a CXCR4+ cell population. Using our parabiotic model, we demonstrated recruitment of CXCR4+ bone marrow-derived mesenchymal stem cells, identified based on marker expression, to irradiated lungs. Finally, irradiated mice that received MSX-122 had significant reductions in development of pulmonary fibrosis while AMD3100 did not significantly suppress this fibrotic process.


CONCLUSIONS
CXCR4 inhibition by drugs such as MSX-122 may alleviate potential radiation-induced lung injury, presenting future therapeutic opportunities for patients requiring chest irradiation.
Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia, United States of America ; Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Hui-Kuo G
HK
Shu
Younghyoun
Y
Yoon
Samuel
S
Hong
Kaiming
K
Xu
Huiying
H
Gao
Chunhai
C
Hao
Edilson
E
Torres-Gonzalez
Cardenes
C
Nayra
Mauricio
M
Rojas
Hyunsuk
H
Shim
D000818:Animals; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000080027:Cyclams; D004195:Disease Models, Animal; D005260:Female; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D011658:Pulmonary Fibrosis / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology* / Q000517:prevention & control; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011832:Radiation Injuries / Q000150:complications*; D011833:Radiation Injuries, Experimental; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014057:Tomography, X-Ray Computed
D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; C573792:N,N'-(1,4-phenylenebis(methylene))dipyrimidin-2-amine; D011743:Pyrimidines; D019718:Receptors, CXCR4; C088327:plerixafor