Model development and use of ACE inhibitors for preclinical mitigation of radiation-induced injury to multiple organs. Radiat Res 2014 Nov;182(5):545-55
Date
11/02/2014Pubmed ID
25361399Pubmed Central ID
PMC4261643DOI
10.1667/RR13425.1Scopus ID
2-s2.0-84914166194 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
The NIH/NIAID initiated a countermeasure program to develop mitigators for radiation-induced injuries from a radiological attack or nuclear accident. We have previously characterized and demonstrated mitigation of single organ injuries, such as radiation pneumonitis, pulmonary fibrosis or nephropathy by angiotensin converting enzyme (ACE) inhibitors. Our current work extends this research to examine the potential for mitigating multiple organ dysfunctions occurring in the same irradiated rats. Using total body irradiation (TBI) followed by bone marrow transplant, we tested four doses of X radiation (11, 11.25, 11.5 and 12 Gy) to develop lethal late effects. We identified three of these doses (11, 11.25 and 11.5 Gy TBI) that were lethal to all irradiated rats by 160 days to test mitigation by ACE inhibitors of injury to the lungs and kidneys. In this study we tested three ACE inhibitors at doses: captopril (88 and 176 mg/m(2)/day), enalapril (18, 24 and 36 mg/m(2)/day) and fosinopril (60 mg/m(2)/day) for mitigation. Our primary end point was survival or criteria for euthanization of morbid animals. Secondary end points included breathing intervals, other assays for lung structure and function and blood urea nitrogen (BUN) to assess renal damage. We found that captopril at 176 mg/m(2)/day increased survival after 11 or 11.5 Gy TBI. Enalapril at 18-36 mg/m(2)/day improved survival at all three doses (TBI). Fosinopril at 60 mg/m(2)/day enhanced survival at a dose of 11 Gy, although no improvement was observed for pneumonitis. These results demonstrate the use of a single countermeasure to mitigate the lethal late effects in the same animal after TBI.
Author List
Medhora M, Gao F, Wu Q, Molthen RC, Jacobs ER, Moulder JE, Fish BLMESH terms used to index this publication - Major topics in bold
Angiotensin-Converting Enzyme InhibitorsAnimals
Bone Marrow Transplantation
Dose-Response Relationship, Radiation
Female
Kidney Diseases
Radiation Injuries
Radiation Pneumonitis
Rats
Whole-Body Irradiation