Volume 2, Issue 2

Original research papers



Amandeep Kaur, Nagalaxmi Vemalapally, Grant Severson, Jatinder Gulani, David Bolduc, Maria Moroni

Pages: 75-81

DOI: 10.21175/RadJ.2017.02.017

Received: 10 JAN 2017, Received revised: 10 MAR 2017, Accepted: 15 MAY 2017, Published online: 28 OCT 2017

There is a pressing need to develop animal models as well as treatment appropriate for age-specific radiation injuries. The minipig represents a promising animal model for testing the effects of radiation on the pediatric population. We subjected piglets, age 6 weeks old (corresponding to less than 2 years old in human), to either sham irradiation or to total body irradiation (60Cobalt 0.6 Gy/min) at hematopoietic doses spanning from 1.6 Gy to 2.0 Gy, and determined the dose-survival relationship and course of radiation injury in the presence of minimal supportive care. The LD50/45 was determined to be 1.83 Gy [CI 1.70 – 1.91]. The course of hematopoietic acute radiation syndrome (H-ARS) in the piglet model resembled that of humans, with four distinct phases namely, prodromal phase, latent phase, manifest illness phase, and recovery or death. Kinetics of blood cell loss such as sudden lymphopenia, decline in neutrophil counts preceded by initial granulocytosis, erythrocytopenia, and thrombocytopenia with a characteristic shoulder followed by partial recovery mimicked the expected radiation-induced changes. Moribund animals were characterized by anorexia, lethargy, fever or hypothermia, bleeding, and dyspnea. Upon euthanasia, animals displayed dose dependent bone marrow hypoplasia and hemorrhages in several organs. Granulocyte colony stimulating factor (G-CSF), a countermeasure approved for H-ARS in humans and effective in adult minipig, was tested in the piglets. Administration of G-CSF enhanced survival by 37.5% and reduced both duration as well as nadir of neutropenia. In conclusion, the minipig provides a practical and feasible animal model for H-ARS and development of radiation countermeasures for the pediatric population. te
  1. P. Aebersold, “FDA experience with medical countermeasures under the animal rule,” Adv. Prev. Med., vol. 2012, pp. 1-11, Sep. 2012.
    DOI: 10.1155/2012/507571
    PMid: 21991452
    PMCid: PMC3177089
  2. Guidance for Industry - Nonclinical Safety Evaluation of Pediatric Drug Products, U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Rockville (MD), USA, 2006.
    Retrieved from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/

    Retrieved on: Jan. 4, 2017.
  3. M. M. Swindle et al., “Swine as models in biomedical research and toxicology testing,” Vet. Pathol., vol. 49, no. 4, pp. 344-356, Jul. 2012.
    DOI: 10.1177/0300985811402846
    PMid: 21441112
  4. X. Li et al., “A novel and stable "two-hit" acute lung injury model induced by oleic acid in piglets,” Acta Vet. Scand., vol. 51, p. 17, Mar. 2009.
    DOI: 10.1186/1751-0147-51-17
    PMid: 19331663
    PMCid: PMC2673213
  5. A. J. Liu et al., “Effect of oleic acid-induced acute lung injury and conventional mechanical ventilation on renal function in piglets,” Chin. Med. J. (Engl.), vol. 126, no. 13, pp. 2530-2535, Jul. 2013.
    PMid: 23823829
  6. T. Elliott et al., “Gastrointestinal acute radiation syndrome in Göttingen minipigs (Sus scrofa domestica),” Comp. Med., vol. 64, no. 6, pp. 456-463, Dec. 2014.
    PMid: 25527026
    PMCid: PMC4275081
  7. M. Moroni et al., “Hematological changes as prognostic indicators of survival: similarities between Göttingen minipigs, humans, and other large animal models,” PLOS ONE, vol. 6, no. 9, p. e25210, Sep. 2011.
    DOI: 10.1371/journal.pone.0025210
    PMid: 21969873
    PMCid: PMC3182184
  8. M. Moroni et al., “Hematopoietic radiation syndrome in the Göttingen minipig,” Radiat. Res., vol. 176, no. 1, pp. 89-101, 2011.
    DOI: 10.1667/RR2481.1
    PMid: 21520996
  9. M. Moroni et al., “Accelerated hematopoietic syndrome after radiation doses bridging hematopoietic (H-ARS) and gastrointestinal (GI-ARS) acute radiation syndrome: early hematological changes and systemic inflammatory response syndrome in minipig,” Int. J. Radiat. Biol., vol. 90, no. 5, pp. 363-372, May 2014.
    DOI: 10.3109/09553002.2014.892226
    PMid: 24524283
  10. M. Moroni et al., “Significance of bioindicators to predict survival in irradiated minipigs,” Health Phys., vol. 106, no. 6, pp. 727-733, Jun. 2014.
    DOI: 10.1097/HP.0000000000000109
    PMid: 24776906
    PMCid: PMC4006360
  11. M. Moroni et al., “The Gottingen minipig is a model of hematopoietic acute radiation syndrome: G-colony stimulating factor stimulates hematopoiesis and enhances survival from lethal total-body γ-irradiation,” Int. J. Radiat. Oncol. Biol. Phys., vol. 86, no. 5, pp. 986-992, Aug. 2013.
    DOI: 10.1016/j.ijrobp.2013.04.041
    PMid: 23845847
    PMCid: PMC3710733
  12. C. I. Rios et al., “Building the strategic national stockpile through the NIAID Radiation Nuclear Countermeasures Program,” Drug Dev. Res., vol. 75, no. 1, pp. 23-28, Feb. 2014.
    DOI: 10.1002/ddr.21163
    PMid: 24648046
  13. Guide for the care and use of laboratory animals, 8th ed., ILAR, Washington, (DC), USA, 2011, pp. 1-154.
    Retrieved from: https://grants.nih.gov/grants/olaw/Guide-for-the-Care-and-Use-of-Laboratory-Animals.pdf
    Retrieved on: Jan. 4, 2017.
  14. J. S. Bradley, M. A. Jackson, “The use of systemic and topical fluoroquinolones,” Pediatrics, vol. 128, no. 4, pp. 1034-1045, Oct. 2011.
    DOI: 10.1542/peds.2011-1496
    PMid: 21949152
  15. P. D. Tamma et al., “Combination therapy for treatment of infections with gram-negative bacteria,” Clin. Microbiol. Rev., vol. 25, no. 3, pp. 450-470, Jul. 2012.
    DOI: 10.1128/CMR.05041-11
    PMid: 22763634
    PMCid: PMC3416487
  16. AVMA guidelines for the euthanasia of animals, AVMA, Schaumburg (IL), USA, 2013, p. 50.
    Retrieved from: https://www.avma.org/KB/Policies/Documents/euthanasia.pdf
    Retrieved on: Jan. 4, 2017.
  17. A. L. Carsten, “Acute lethality - the hematopoietic syndrome in different species,” in Response of different species to total body irradiation, vol. 10, Lieden, Netherlands: Brill Publishers, 1984, ch. 1, pp. 59-86.
    DOI: 10.1007/978-94-009-6048-0_5
  18. M. Moroni et al., “Evaluation of the gamma-H2AX assay for radiation biodosimetry in a swine model,” Int. J. Mol. Sci., vol. 14, no. 7, pp. 14119-14135, Jul. 2013.
    DOI: 10.3390/ijms140714119
    PMid: 23880859
    PMCid: PMC3742235
  19. T. Johansen et al., “The obese Göttingen minipig as a model of the metabolic syndrome: dietary effects on obesity, insulin sensitivity, and growth hormone profile,” Comp. Med., vol. 51, no. 2, pp. 150-155, Apr. 2001.
    PMid: 11922179
  20. H. L. Abrams, “Influence of Age, Body Weight, and Sex on Susceptibility of Mice to the Lethal Effects of X-radiation,” Exp. Biol. Med., vol. 76, pp. 729-732, Apr. 1951.
    DOI: 10.3181/00379727-76-18610
  21. D. C. Jones et al., “Age at x-irradiation and acute mortality in the adult male rat,” Rad. Res., vol. 38, no. 3, pp. 614-621, Jun. 1969.
    DOI: 10.2307/3572620
    PMid: 5790124
  22. B. Patel et al., “Mobilisation of haematopoietic stem cells in paediatric patients, prior to autologous transplantation following administration of plerixafor and G-CSF,” Pediatr. Blood Cancer, vol. 62, no. 8, pp. 1477-1480, Aug. 2015.
    DOI: 10.1002/pbc.25467
    PMid: 25755177
  23. A. M. Farese et al., “Filgrastim improves survival in lethally irradiated nonhuman primates,” Rad. Res., vol. 179, no. 1, pp. 89-100, Jan. 2013.
    DOI: 10.1667/RR3049.1
    PMid: 23210705
    PMCid: PMC4562422
  24. M. F. Ozkaynak et al., “Randomized comparison of antibiotics with and without granulocyte colony-stimulating factor in children with chemotherapy-induced febrile neutropenia: A report from the children’s Oncology group,” Pediatr. Blood Cancer, vol. 45, no. 3, pp. 274-280, Sep. 2005.
    DOI: 10.1002/pbc.20366
    PMid: 15806544