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

Public Health Relevance

The threat of a nuclear disaster on U.S. soil is high. Currently, there is no effective treatment strategy to mitigate radiation-induced lung injury after exposure. We have developed a mangano porphyrin antioxidant compound that has the ability to reduce oxidative stress, inflammation, fibrosis, and overall functional injury when given after exposure to ionizing radiation. Thus, there is an opportunity to develop effective treatment strategy for victims of a nuclear attack or accident. The goal of this proposal is to complete development of a safe and effective medical product to treat radiation-induced lung injury and make it available for stockpiling.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
NIH Challenge Grants and Partnerships Program (RC1)
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Special Emphasis Panel (ZAI1-JSR-I (S4))
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Dicarlo-Cohen, Andrea L
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Duke University
Schools of Medicine
United States
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Xu, P-T; Maidment 3rd, B W; Antonic, V et al. (2016) Cerium Oxide Nanoparticles: A Potential Medical Countermeasure to Mitigate Radiation-Induced Lung Injury in CBA/J Mice. Radiat Res 185:516-26
Murigi, Francis N; Mohindra, Pranshu; Hung, Chiwei et al. (2015) Dose Optimization Study of AEOL 10150 as a Mitigator of Radiation-Induced Lung Injury in CBA/J Mice. Radiat Res 184:422-32