Establishing a murine model of the hematopoietic syndrome of the acute radiation syndrome

P. Artur Plett, Carol H. Sampson, Hui Lin Chua, Mandar Joshi, Catherine Booth, Alec Gough, Cynthia S. Johnson, Barry P. Katz, Ann M. Farese, Jeffrey Parker, Thomas J. MacVittie, Christie M. Orschell

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Abstract

The authors have developed a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS) for efficacy testing of medical countermeasures (MCM) against radiation according to the FDA Animal Rule. Ten- to 12-wk-old male and female C57BL/6 mice were exposed to the LD50/30-LD70/30 dose of total body irradiation (TBI, 137Cs, 0.62-0.67 Gy min -1) in the morning hours when mice were determined to be most radiosensitive, and they were assessed for 30-d survival and mean survival time (MST). Antibiotics were delivered in drinking water on days 4-30 post-TBI at a concentration based on the amount of water that lethally-irradiated mice were found to consume. The fluoroquinolones, ciprofloxacin and levofloxacin, as well as the tetracycline doxycycline, and aminoglycoside neomycin, all significantly increased MST of decedent mice, while ciprofloxacin (p = 0.061) and doxycycline + neomycin (p = 0.005) showed at least some efficacy to increase 30-d survival. Blood sampling (30 μL/mouse every fifth day) was found to negatively impact 30-d survival. Histopathology of tissues harvested from nonmoribund mice showed expected effects of lethal irradiation, while moribund mice were largely septicemic with a preponderance of enteric organisms. Kinetics of loss and recovery of peripheral blood cells in untreated mice and those treated with two MCM, granulocyte-colony stimulating factor and Amifostine further characterized and validated this model for use in screening studies and pivotal efficacy studies of candidate MCM for licensure to treat irradiated individuals suffering from H-ARS.

Original languageEnglish (US)
Pages (from-to)343-355
Number of pages13
JournalHealth physics
Volume103
Issue number4
DOIs
StatePublished - Oct 1 2012

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Keywords

  • blood mice
  • Dose assessment
  • modeling
  • radiation dose

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Health, Toxicology and Mutagenesis
  • Epidemiology

Cite this

Plett, P. A., Sampson, C. H., Chua, H. L., Joshi, M., Booth, C., Gough, A., Johnson, C. S., Katz, B. P., Farese, A. M., Parker, J., MacVittie, T. J., & Orschell, C. M. (2012). Establishing a murine model of the hematopoietic syndrome of the acute radiation syndrome. Health physics, 103(4), 343-355. https://doi.org/10.1097/HP.0b013e3182667309