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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...

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Autores principales: Shu, Hui-Kuo G., Yoon, Younghyoun, Hong, Samuel, Xu, Kaiming, Gao, Huiying, Hao, Chunhai, Torres-Gonzalez, Edilson, Nayra, Cardenes, Rojas, Mauricio, Shim, Hyunsuk
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820649/
https://www.ncbi.nlm.nih.gov/pubmed/24244561
http://dx.doi.org/10.1371/journal.pone.0079768
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author Shu, Hui-Kuo G.
Yoon, Younghyoun
Hong, Samuel
Xu, Kaiming
Gao, Huiying
Hao, Chunhai
Torres-Gonzalez, Edilson
Nayra, Cardenes
Rojas, Mauricio
Shim, Hyunsuk
author_facet Shu, Hui-Kuo G.
Yoon, Younghyoun
Hong, Samuel
Xu, Kaiming
Gao, Huiying
Hao, Chunhai
Torres-Gonzalez, Edilson
Nayra, Cardenes
Rojas, Mauricio
Shim, Hyunsuk
author_sort Shu, Hui-Kuo G.
collection PubMed
description 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: CXCR4 inhibition by drugs such as MSX-122 may alleviate potential radiation-induced lung injury, presenting future therapeutic opportunities for patients requiring chest irradiation.
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spelling pubmed-38206492013-11-15 Inhibition of the CXCL12/CXCR4-Axis as Preventive Therapy for Radiation-Induced Pulmonary Fibrosis Shu, Hui-Kuo G. Yoon, Younghyoun Hong, Samuel Xu, Kaiming Gao, Huiying Hao, Chunhai Torres-Gonzalez, Edilson Nayra, Cardenes Rojas, Mauricio Shim, Hyunsuk PLoS One Research Article 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: CXCR4 inhibition by drugs such as MSX-122 may alleviate potential radiation-induced lung injury, presenting future therapeutic opportunities for patients requiring chest irradiation. Public Library of Science 2013-11-07 /pmc/articles/PMC3820649/ /pubmed/24244561 http://dx.doi.org/10.1371/journal.pone.0079768 Text en © 2013 Shu et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Shu, Hui-Kuo G.
Yoon, Younghyoun
Hong, Samuel
Xu, Kaiming
Gao, Huiying
Hao, Chunhai
Torres-Gonzalez, Edilson
Nayra, Cardenes
Rojas, Mauricio
Shim, Hyunsuk
Inhibition of the CXCL12/CXCR4-Axis as Preventive Therapy for Radiation-Induced Pulmonary Fibrosis
title Inhibition of the CXCL12/CXCR4-Axis as Preventive Therapy for Radiation-Induced Pulmonary Fibrosis
title_full Inhibition of the CXCL12/CXCR4-Axis as Preventive Therapy for Radiation-Induced Pulmonary Fibrosis
title_fullStr Inhibition of the CXCL12/CXCR4-Axis as Preventive Therapy for Radiation-Induced Pulmonary Fibrosis
title_full_unstemmed Inhibition of the CXCL12/CXCR4-Axis as Preventive Therapy for Radiation-Induced Pulmonary Fibrosis
title_short Inhibition of the CXCL12/CXCR4-Axis as Preventive Therapy for Radiation-Induced Pulmonary Fibrosis
title_sort inhibition of the cxcl12/cxcr4-axis as preventive therapy for radiation-induced pulmonary fibrosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820649/
https://www.ncbi.nlm.nih.gov/pubmed/24244561
http://dx.doi.org/10.1371/journal.pone.0079768
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