Inhibition of the CXCL12/CXCR4-Axis as Preventive Therapy for Radiation-Induced Pulmonary Fibrosis

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.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…Robust upregulation in serum and BAL CXCL12 levels following injury highlighted that the CXCR4/CXCL12 axis mediates MSC recruitment. Contrary to the previous study, inhibition of MSC recruitment with a CXCR4 antagonist attenuated radiation-induced fibrosis (Shu et al, 2013).…”

“…Whether bone marrow (BM) MSCs circulate in humans has been the subject of debate (Hoogduijn et al, 2014;Mansilla et al, 2006;Wang et al, 2006). Despite this, recent studies conducted in animal models of injury have provided robust evidence that endogenous bone marrow-derived stromal cells can circulate and localise in injured tissue (Chen et al, 2010;Gao et al, 2014;Hong et al, 2009;Shu et al, 2013). In a study by Gao et al, endogenous Nestin+ MSCs were recruited to the lungs of Nes-GFP-transgenic mice challenged intranasally with cockroach allergen.…”

Radiation-induced pulmonary injury accelerated pulmonary metastasis in a mouse model of breast cancer

“…It has been reported that the activation of the CXCL12/CXCR4 axis was important in the development of radiation-induced pulmonary fibrosis (14). The CXCL12/CXCR4 axis participated in the vascularization induced by radiation and was closely associated with the recurrence and metastasis of breast cancer subsequent to radiation.…”

“…It has previously been reported that activation of the chemotactic receptor CXCR4 by the ligand CXCL12 was important in the development of radiation-induced pulmonary fibrosis (14). Subsequent to radiation-induced injury, bone marrow-derived fibroblast progenitor cells, also termed fibrocytes, which express CXCR4, are recruited to regions of fibrosis in the lung (25,31).…”

Role of CXCL12/CXCR4-Mediated Circulating Fibrocytes in Pulmonary Fibrosis

“…Several small molecule CXCR4 antagonists (e.g. AMD3100, MSX-122, TN14003) have been developed and some of them significantly reduced bleomycin or radiation-induced pulmonary fibrosis in mice 48,[73][74][75] . Plerixafor (solution of AMD3100 for subcutaneous injection, brand name: Mozobil™, Genzyme Corporation) has been approved by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in hematopoietic stem cells (HSC) mobilization for autologous transplant for patients with non-Hodgkin's lymphoma and multiple myeloma (MM) 76 .…”