Blockade of the SDF-1/CXCR4 axis as a novel strategy for mitigating radiation-ind

Emory University, Atlanta GA

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Abstract

Summary Either total body exposure to ionizing radiation or inhalation of radioactive particulates can result in significant radiation dose deposition to the lungs. While a number of side effects can be observed from this type of exposure, pulmonary fibrosis is a particularly devasting outcome that results from the injury caused by radiation. This problem develops as progressive shortness of breath with increasing interstitial lung fibrosis and loss of alveolar structures. Thus, development of a therapy that can block the onset of this late radiation effect can be of great benefit to subjects that may undergo non-therapeutic exposure to radiation. Stromal cell- derived factor 1 (SDF-1/CXCL12) is a chemokine that, through interactions with its receptor CXCR4, may play an important role in this radiation-ionduced fibrotic response through recruitment of bone marrow-derived progenitor cells to the injured lung. The chemotaxis of these cells to an area of lung injury is believed to be a critical step in the ultimate development of pulmonary fibrosis. In mouse models of bleomycin-induced pulmonary fibrosis, inhibitors of CXCR4 can significantly decrease the development of lung fibrosis. We have recently developed a safe inhibitor of CXCR4 (WZ40) that binds in the nM range and shows no evidence of the toxicities that have been observed with previously available CXCR4 antagonists. In our preliminary work, we also find that WZ40 can block bleomycin-induced lung fibrosis. Although the latency period for development of lung fibrosis after radiation exposure is longer than that observed with bleomycin, we hypothesize that radiation-induced fibrosis likely occurs via a similar mechanism to that induced by the lung-toxic chemotherapy agent and involves recruitment of CXCR4+ bone marrow-derived progenitor cells. Thus, we believe that CXCR4 inhibition will also inhibit pulmonary fibrosis after exposure of the lungs to irradiation and may function as an effective mitigator of this toxicity. In this proposal, we seek to assess the efficacy of WZ40 as a mitigator of this process in a mouse model of radiation-induced pulmonary fibrosis. Thus far, WZ40 appears to be an ideal drug for use in this role based on its high oral bioavailability and its apparent low toxicity. The primary goal of this study is to determine the potential utility of this new drug in the prevention of radiation-induced pulmonary fibrosis and to establish a rationale for the clinical evaluation of WZ40 for this problem.