Our goals for this Project will be to develop countermeasures to effectively mitigate and treat radiation-induced pneumonitis and pulmonary fibrosis in rodents. Specifically we propose to accelerate development of FDA-approved Angiotensin Converting Enzyme inhibitors (ACEi), captopril, enalapril or fosinopril for safe and effective mitigation and treatment. Additionally we will test one selected ACEi in combination with either a free radical scavenger EUK-207 or an anti-inflammatory soluble epoxide hydrolase inhibitor (sEHi), 1471. We will use 2 relevant models of injury to test countermeasures: a single dose of 10 Gy total body irradiation (TBI) for pneumonitis;and >12 Gy localized thoracic irradiation for pulmonary fibrosis. The doses and models we propose simulate conditions that may be survivable with supportive care following exposure to a radiological or nuclear attack. Our product development milestones are to: 1) Identify a safe and effective ACEi with optimal duration of administration for mitigation and treatment of pneumonitis - timeline by 6-8 months from start;2) Determine efficacy of agents EUK-207 or sEHi1471 in combination with the ACE inhibitor for mitigation and treatment of pneumonitis - timeline 6-12 months from start;3) Determine the effect of ACEi on mitigation of radiation-induced fibrosis in the lung - 12 months from start;4) Confirm the most effective mitigating regimen in juvenile animals and rats of both sexes - timeline 13-15 months from start;5) Determine the dose modification factor (DMF) of the most effective mitigating regimen - timeline 13-15 months from start;and 6) Test the most effective mitigating regimen in a second rodent species, mice (in collaboration).
Our aims are designed to satisfy the goal of this RFA to accelerate research and development of promising medical products, for mitigation and treatment of radiation-induced pulmonary injury.
Currently there are no approved treatments for non-lethal injuries caused by a nuclear explosion. We propose to accelerate research and development of a very promising medical product that is currently widely used for heart disease, to treat injury that develops in the lungs of such victims. A few laboratories including ours have demonstrated that the drug captopril is effective against injuries to rat lungs, kidneys, brain and skin, after exposure to radiation. In our experiments we apply radiation only once, a schedule that is designed to mimic a nuclear attack. We have observed conclusively, that captopril fed after exposure is able to counter injuries that develop months later. Captopril has been approved by the FDA for treatment of high blood pressure, kidney failure following diabetes, heart attacks and other prevailing ailments. The effective dose of captopril in our studies is within the range approved by the FDA, however it is high and may not be safe for victims unless they are monitored carefully during treatment. Therefore we propose to test related compounds for safe use and will also determine combinations of these compounds at lower doses with other unrelated but effective countermeasures. After identifying the safest agents against lung injury to rats, we will confirm our studies in animals of all ages and gender and also in mice. This study will rapidly move forward the use of already developed drugs to protect humans against the devastating effects of a nuclear attack or accident, or exposure to a dirty bomb.
|Densmore, John C; Schaid, Terry R; Jeziorczak, Paul M et al. (2017) Lung injury pathways: Adenosine receptor 2B signaling limits development of ischemic bronchiolitis obliterans organizing pneumonia. Exp Lung Res 43:38-48
|Medhora, Meetha; Haworth, Steven; Liu, Yu et al. (2016) Biomarkers for Radiation Pneumonitis Using Noninvasive Molecular Imaging. J Nucl Med 57:1296-301
|Fish, Brian L; Gao, Feng; Narayanan, Jayashree et al. (2016) Combined Hydration and Antibiotics with Lisinopril to Mitigate Acute and Delayed High-dose Radiation Injuries to Multiple Organs. Health Phys 111:410-9
|Medhora, Meetha; Gao, Feng; Glisch, Chad et al. (2015) Whole-thorax irradiation induces hypoxic respiratory failure, pleural effusions and cardiac remodeling. J Radiat Res 56:248-60
|Gao, Feng; Fish, Brian L; Szabo, Aniko et al. (2014) Enhanced survival from radiation pneumonitis by combined irradiation to the skin. Int J Radiat Biol 90:753-61
|Moulder, John E; Cohen, Eric P; Fish, Brian L (2014) Mitigation of experimental radiation nephropathy by renin-equivalent doses of angiotensin converting enzyme inhibitors. Int J Radiat Biol 90:762-8
|Medhora, Meetha; Gao, Feng; Wu, Qingping et al. (2014) Model development and use of ACE inhibitors for preclinical mitigation of radiation-induced injury to multiple organs. Radiat Res 182:545-55
|Gao, Feng; Fish, Brian L; Moulder, John E et al. (2013) Enalapril mitigates radiation-induced pneumonitis and pulmonary fibrosis if started 35 days after whole-thorax irradiation. Radiat Res 180:546-52
|Down, Julian D; Medhora, Meetha; Jackson, Isabel L et al. (2013) Do variations in mast cell hyperplasia account for differences in radiation-induced lung injury among different mouse strains, rats and nonhuman primates? Radiat Res 180:216-21
|Gao, Feng; Narayanan, Jayashree; Joneikis, Cortney et al. (2013) Enalapril mitigates focal alveolar lesions, a histological marker of late pulmonary injury by radiation to the lung. Radiat Res 179:465-74
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