title: Establishing a murine model of the hematopoietic syndrome of the acute radiation syndrome.
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, (137)Cs, 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.
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: P Artur
authors.initials: PA
authors.lastname: Plett
authors.forename: Carol H
authors.initials: CH
authors.lastname: Sampson
authors.forename: Hui Lin
authors.initials: HL
authors.lastname: Chua
authors.forename: Mandar
authors.initials: M
authors.lastname: Joshi
authors.forename: Catherine
authors.initials: C
authors.lastname: Booth
authors.forename: Alec
authors.initials: A
authors.lastname: Gough
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Johnson
authors.forename: Barry P
authors.initials: BP
authors.lastname: Katz
authors.forename: Ann M
authors.initials: AM
authors.lastname: Farese
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Parker
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: MacVittie
authors.forename: Christie M
authors.initials: CM
authors.lastname: Orschell
mesh_terms: D054508:Acute Radiation Syndrome / Q000209:etiology* / Q000503:physiopathology*; D000818:Animals; D002470:Cell Survival / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006412:Hematopoietic Stem Cells / Q000528:radiation effects*; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000209:etiology* / Q000503:physiopathology*; D016019:Survival Analysis; D015996:Survival Rate; D014916:Whole-Body Irradiation / Q000009:adverse effects*