Abstract
BackgroundA 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 FindingsThe 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/SignificanceCXCR4 inhibition by drugs such as MSX-122 may alleviate potential radiation-induced lung injury, presenting future therapeutic opportunities for patients requiring chest irradiation.
Highlights
Cancer therapy may require radiation treatment in the chest, potentially resulting in significant dose to lung tissue
computed tomography (CT)-based fibrosis assessment correlates to histology in hemithoracic radiation-induced pulmonary fibrosis (PF) model
Development of a therapy to prevent the development of PF could be of great benefit for at-risk patient populations
Summary
Cancer therapy may require radiation treatment in the chest, potentially resulting in significant dose to lung tissue These patients are at risk for developing lung radiation injury including pulmonary fibrosis (PF), an incurable, late radiation toxicity that can cause significant morbidity and even mortality depending on the volume of lung affected (For review, see [1]). Neutralizing antibody against CXCL12 can prevent the recruitment of circulating fibrocytes to bleomycin-damaged lung and suppress the development of fibrosis [4] Further characterization of these BM-derived cells demonstrate expression of the mesenchymal stem cell markers CD44 and CD105 in addition to CXCR4 but lack of the hematopoetic stem cell marker CD45 [5]. 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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