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Delayed Captopril Administration Mitigates Hematopoietic Injury in a Murine Model of Total Body Irradiation
- Source :
- Scientific Reports, Scientific Reports, Vol 9, Iss 1, Pp 1-13 (2019)
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- The increasing potential for accidental radiation exposure from either nuclear accidents or terrorist activities has escalated the need for radiation countermeasure development. We previously showed that a 30-day course of high-dose captopril, an ACE inhibitor, initiated 1–4 h after total body irradiation (TBI), improved Hematopoietic Acute Radiation Syndrome (H-ARS) and increased survival in mice. However, because of the time likely required for the deployment of a stockpiled radiation countermeasure to a radiation mass casualty site, there is a need for therapies that can be administered 24–48 hours after initial exposure. Using C57BL/6 mice exposed to an LD50-80/30 of 60Co TBI (7.75–7.9 Gy, 0.615 Gy/min), we show that low-dose captopril administration, initiated as late as 48 h post-TBI and continued for 14 days, significantly enhanced overall survival similarly to high-dose, rapid administration. Captopril treatment did not affect radiation-induced cell cycle arrest genes or the immediate loss of hematopoietic precursors. Reduced mortality was associated with the recovery of bone marrow cellularity and mature blood cell recovery at 21–30 days post-irradiation. Captopril reduced radiation-induced cytokines EPO, G-CSF, and SAA in the plasma. Finally, delayed captopril administration mitigated brain micro-hemorrhage at 21 days post-irradiation. These data indicate that low dose captopril administered as late as 48 h post-TBI for only two weeks improves survival that is associated with hematopoietic recovery and reduced inflammatory response. These data suggest that captopril may be an ideal countermeasure to mitigate H-ARS following accidental radiation exposure.
- Subjects :
- 0301 basic medicine
Captopril
Cell cycle checkpoint
lcsh:Medicine
Angiotensin-Converting Enzyme Inhibitors
Radiation-Protective Agents
Pharmacology
Radiation Dosage
Article
Time-to-Treatment
Blood cell
Mice
03 medical and health sciences
0302 clinical medicine
medicine
Animals
lcsh:Science
Multidisciplinary
Dose-Response Relationship, Drug
business.industry
lcsh:R
Cell Cycle
Acute Radiation Syndrome
Dose-Response Relationship, Radiation
Radiation Exposure
Total body irradiation
Hematopoietic Stem Cells
Blood Cell Count
Hematopoiesis
Disease Models, Animal
Haematopoiesis
Dose–response relationship
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
ACE inhibitor
Cytokines
lcsh:Q
Inflammation Mediators
business
Whole-Body Irradiation
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....04546e112d4733007ff368465ba3c5e8