Either total body exposure to ionizing radiation or inhalation of radioactive particulates can result in significantradiation dose deposition to the lungs. While a number of side effects can be observed from this type ofexposure, pulmonary fibrosis is a particularly devasting outcome that results from the injury caused byradiation. This problem develops as progressive shortness of breath with increasing interstitial lung fibrosisand loss of alveolar structures. Thus, development of a therapy that can block the onset of this late radiationeffect 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 playan important role in this radiation-ionduced fibrotic response through recruitment of bone marrow-derivedprogenitor cells to the injured lung. The chemotaxis of these cells to an area of lung injury is believed to be acritical step in the ultimate development of pulmonary fibrosis. In mouse models of bleomycin-inducedpulmonary fibrosis, inhibitors of CXCR4 can significantly decrease the development of lung fibrosis. We haverecently developed a safe inhibitor of CXCR4 (WZ40) that binds in the nM range and shows no evidence of thetoxicities that have been observed with previously available CXCR4 antagonists. In our preliminary work, wealso find that WZ40 can block bleomycin-induced lung fibrosis. Although the latency period for development oflung fibrosis after radiation exposure is longer than that observed with bleomycin, we hypothesize thatradiation-induced fibrosis likely occurs via a similar mechanism to that induced by the lung-toxic chemotherapyagent and involves recruitment of CXCR4+ bone marrow-derived progenitor cells. Thus, we believe thatCXCR4 inhibition will also inhibit pulmonary fibrosis after exposure of the lungs to irradiation and may functionas an effective mitigator of this toxicity. In this proposal, we seek to assess the efficacy of WZ40 as a mitigatorof this process in a mouse model of radiation-induced pulmonary fibrosis. Thus far, WZ40 appears to be anideal drug for use in this role based on its high oral bioavailability and its apparent low toxicity. The primarygoal of this study is to determine the potential utility of this new drug in the prevention of radiation-inducedpulmonary fibrosis and to establish a rationale for the clinical evaluation of WZ40 for this problem.
The goal of this proposal is to evaluate a new drug for its ability to suppress the development of radiation- induced pulmonary fibrosis. Because of better supportive medical care for subjects that have undergone high total body exposure to radiation, such patients are now able to survive the bone marrow and GI toxicities that they might have previously succumbed to. Thus, such patients can now survive these total body exposures and will be more likely to develop other devastating late toxicities such as pulmonary fibrosis. If successful, this drug will be further evaluated in clinical trials to attempt to define its use as a mitigator of radiation-induced pulmonary fibrosis.
| Shu, Hui-Kuo G; Yoon, Younghyoun; Hong, Samuel et al. (2013) Inhibition of the CXCL12/CXCR4-axis as preventive therapy for radiation-induced pulmonary fibrosis. PLoS One 8:e79768 |
