Antioxidant Mimetic as a Mitigator of Radiation Induced Lung Injury

Duke University, Durham NC

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Abstract

The goal of this project is to establish an effective, practical, and widely available medical countermeasure to mitigate radiation-induced lung injury by utilizing metalloporphyrin antioxidant mimetic based strategies. This project is strongly focused on the Mn-TE-2-PyP compound, a manganese containing meso-porphyrin which scavenges oxygen derived free radicals, for use in mass casualty settings. Experience with nuclear accident victims demonstrates pulmonary toxicity to be the major cause of death when the hematopoietic and gastrointestinal syndromes are successfully treated. Therefore, the development of a therapeutic strategy to reduce pneumonitis/fibrosis and to preserve lung function after radiation exposure is paramount to increasing overall survival in the event of a nuclear attack. It is now known that oxygen derived free radicals, which facilitate inflammation and participate in profibrotic signaling pathways, are a major underlying cause of radiation induced lung damage and that ionizing radiation inactivates endogenous antioxidant defense mechanisms impairing the ability of the exposed tissue to counterbalance the increased production of free radicals. Our studies have shown that radiation-induced oxidative stress, inflammation and profibrogenic/proangiogenic cytokine production within the pulmonary environment are significantly reduced with long-term delivery of Mn-TE-2-PyP. Furthermore, metalloporphyrin antioxidant mimetic, Mn-TE-2-PyP has shown potential to mitigate radiation-induced lung injury when given 2 hours, and possibly up to 8 weeks after irradiation. We now propose to determine the optimum dose level and duration of treatment to optimize mitigation of lung injury and to determine the length of the window of opportunity for initiation of treatment to achieve the most effective mitigation. We will also confirm the efficacy of this antioxidant in a second rodent model of upper-body irradiation. Finally we will complete the drug development program for this antioxidant and bring it to an IND application so that human safety trials can be initiated.