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USU Dept. of Radiation Biology
You are here:  HOME  >  Research Programs  >  Combined Injury: Radiation with Other Insults

Combined Injury: Radiation with Other Insults

Jump to:  Background | Research protocols | Collaborations | 5-year plan | Accomplishments
Overview
Mission: To develop medical treatments for irradiated personnel whose exposure is compounded by traumatic wounds, burns, hemorrhage, and/or infection. Treatment strategies under investigation include biological response modifiers, new antimicrobial agents, probiotics, and stem cells, used individually or in combination.
Symposium, radiation combined injury
 
Principal Investigators: William F. Blakely, PhD; David L. Bolduc, PhD; Juliann G. Kiang, PhD; R. Joel Lowy, PhD; Natalia I. Ossetrova, PhD; Joshua M. Swift, LT, USN, PhD
 
Staff: Marsha Anderson, HM1, USN; True M. Burns, MS; Georgetta Cannon, PhD; Donald Condliffe; Risaku Fukumoto, PhD; Kevin Hieber; Erin Horton; Aminul Islam, PhD; Katya Krasnopolsky; Michelle Metrinko; Patrick Ney; Rossita Owens; Phyllis Reese, MS; Joan T. Smith; Min Zhai, MD
     
Strategic plan
  • Develop a comprehensive understanding of the biology of radiation injury combined with traumatic wounds, burns, hemorrhage, or infections.
  • Establish a good understanding of countermeasure drugs for radiation, wounding, burn, hemorrhage, or infection.
  • Use knowledge of processes involved in radiation combined injury and countermeasures to identify and assess novel drug candidates.
  • Collaborate proactively with other research institutions, pharmaceutical firms, and government agencies to develop and obtain approval for promising countermeasures for use in the field and the clinic.
Background
The Radiation Injury Combined with Other Trauma Program, since being established in 2007, has reached the following findings:
  • Ionizing radiation causes morbidity and mortality.
  • Mortality is caused by damage to the blood-forming system or the gastrointestinal (GI) system.
  • In the mouse model, mortality caused by exposure to less than 10-Gy radiation is due to the damage in the blood-forming system.
  • Mortality caused by exposure to greater than 10-Gy radiation is due to the damage in the GI system.
  • Trauma from wounds, burns, or bacterial infections increases ionizing radiation-induced mortality and its onset is much earlier than ionizing radiation alone.
  • Increased mortality is due to excessive iNOS activation, excessive cytokine concentrations, and excessive systemic bacterial infection that lead to multiple organ dysfunction syndrome and multiple organ failure.
  • Radiation injury combined with wound trauma thins ileal villi and serosa layers (figure 1).
              Figure 1. Thinner villie and serosa layers are observed in ileum of mice with radiation combined injury.
  Figure 1. Thinner villi and serosa layers (as indicated by arrows) are observed in ileum of mice with radiation combined injury. RI: radiation injury; CI: radiation combined injury (Kiang et al., Radiat Res. 173:319–332, 2010)
  • Radiation injury combined with wound trauma results in a smaller healing bud at the wound site (figure 2).
  Figure 2: smaller healing bud
  Figure 2. A smaller healing bud (as indicated by arrows) is observed in skin of mice with radiation combined injury. RI: radiation injury; CI: radiation combined injury (Kiang et al., Radiat Res. 173:319–332, 2010)
  • Possible countermeasures to ionizing radiation compounded with other injuries can be broadly categorized into three groups:
    1. Drugs that prevent the initial radiation injury (prophylaxis)
      • Free radical antioxidants
      • Hypoxia
      • Enzymatic detoxification
      • Oncogene targeting agents
    2. Drugs that repair the molecular damage caused by radiation (mitigation)
      • Hydrogen transfer
      • Enzymatic repair
      • micro-RNA
    3. Drugs that stimulate proliferation of surviving stem and progenitor cells (therapy)
      • Immunomodulators
      • Growth factors and cytokines
      • micro-RNA
  • Treatment with COX-2 inhibitors (e.g., celecoxib, meloxicam), iNOS inhibitors (e.g., NIL6, 5-AED, 17-DMAG), or immunomodulators and antibiotics (e.g., S-TDCM + levofloxacin) before lethal ionizing radiation has shown to protect mice from radiation-induced mortality. When these drugs are administered to mice after radiation combined injury, they fail to improve mouse survival. Therefore, to treat radiation combined injury, a series of treatments with mitigators and therapeutics at various time points after injury should be considered.
  • Military personnel and emergency responders urgently need nontoxic countermeasures to radiation combined injury.
  • The only approved countermeasures that can be used in the field are drugs that block the effects of several specific internalized radioisotopes. There are no approved drugs that can be used outside the clinic to ameliorate the effects of external ionizing radiation combined injury on the blood-forming or GI systems.
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Research protocols
AFRRI researchers have examined the efficacy, toxicity, and molecular mechanisms of a number of radiation countermeasure candidates. The research has been supported by intramural and extramural grants.
  • Intramural grants—AFRRI
  • Extramural grants—NIAID/NIH, DTRA, and DMRDP
Collaborations
This research program includes the following scientific collaborations:
  • MJ Daly, Uniformed Services University of the Health Sciences (USUHS)
  • PD Bowman, U.S. Army Institute of Surgical Research
  • JL Atkins, Walter Reed Army Institute of Research
  • KT Tsen and OF Sanky, Arizona State University
  • TC Wu, Johns Hopkins University
  • S Zou and G Lee, National Institute of Aging, NIH
  • M Yamin, Araim Pharmaceuticals, Inc.
  • Alexion Pharmaceuticals, Inc.
  • RK Maheshwari, USUHS
  • Onconova Therapeutics, Inc.
Five-year plan
The program's five-year goals include the following:
  1. Develop more models for studying radiation combined injury.
  2. Understand molecular mechanisms underlying radiation combined injury.
  3. Establish regimens for protecting from, mitigating, and treating radiation combined injury.
Accomplishments (2007–present)
Patent applications
The following patent applications have been filed:
  1. System and method for diminishing the function of microorganisms with a visible femtosecond laser (Tsen KT, Tsen SWD, and Kiang JG, U.S. Patent 60,932,668, 1 Jun 2008)
  2. 17-DMAG as a radioprotectant (Kiang JG, U.S. Provisional Patent 2001798.126, 11 Dec 2008)
Papers published
2014
  1. Kiang JG, Fukumoto R (2014) Ciprofloxacin increases survival after ionizing irradiation combined injury: Gamma-h2ax formation, cytokine/chemokine, and red blood cells. Health Phys. 106:720–726.
  2. Kiang JG, Garrison BR, Smith JT, Fukumoto R (2014) Ciprofloxacin as a potential radio-sensitizer to tumor cells and a radio-protectant for normal cells: Differential effects on γ-H2AX formation, p53 phosphorylation, Bcl-2  production, and cell death. Mol Cell Biochem (in press). 
  3. Fukumoto R, Burns TM, Kiang JG (2014) Ciprofloxacin enhances stress erythropoiesis in spleen and increases survival after whole-body irradiation combined with skin-wound trauma. PLoS One 9(2):e90448.
  4. Kiang JG, Zhai M, Liao P-J, Bolduc DL, Elliott TB, Gorbunov NV (2014) Pegylated G-CSF inhibits blood cell depletion, increases platelets, blocks splenomegaly, and improves survival after whole-body ionizing irradiation but not after irradiation combined with burn. Oxid Med Cell Longev. 2014: 481392 (10 pages).
2013
  1. Fukumoto R, Cary LH, Gorbunov NV, Lombardini ED, Elliott TB, Kiang JG (2013) Ciprofloxacin modulates cytokine/chemokine profile in serum, improves bone marrow repopulation, and limits apoptosis and autophagy in ileum after whole body ionizing irradiation combined with skin-wound trauma. PLoS One 8: e58389.
  2. Gorbunov NV, Garrison BR, McDaniel DP, Zhai M, Liao P-J, Nurmemet N, Kiang JG (2013) Adaptive redox response of mesenchymal stromal cells to stimulation with Lipopolysaccharide inflammagen: Mechanisms of remodeling of tissue barriers in sepsis. J Oxidative Med and Cell Longevity, volume 2013, Article ID 186795, 16 pages.
  3. Kiang JG, Ledney GD (2013) Skin injuries reduce survival and modulate corticosterone, C-reactive protein, complement component 3, IgM, and prostaglandin E 2 after whole-body reactor-produced mixed field (n + γ-photons) irradiation. Oxid Med Cell Longev. 2013; 2013:821541 (10 pages).
  4. Lu X, Nurmemet D, Bolduc DL, Elliott TB, Kiang JG (2013) Radioprotective effects of oral 17-dimethylaminoethylamino-17-demethoxygeldanamycin in mice: Bone marrow and small intestine. Cell Biosci. 3:36 (16 pages).
2012
  1. Gorbunov NV, Garrison BR, Zhai M, McDaniel DP, Ledney GD, Elliott TB, Kiang JG (2012) Autophagy-mediated defense response of mouse mesenchymal stromal cells (MSCs) to challenge with Escherichia coli. In: Cai J. (ed.) Protein Interaction/Book 1; ISBN 979-953-307-577-7. InTech Open Access Publisher. Pages 23–44.
  2. Kiang JG, Fukumoto R, Gorbunov NV (2012) Lipid peroxidation after ionizing irradiation leads to apoptosis and autophagy. In: Angel Catala (ed.) Lipid Peroxidation; ISBN 980-953-307-143-0. InTech Open Access Publisher: www.intechweb.org. Pages 261–278.
  3. Kiang JG, Garrison BR, Burns TM, Zhai M, Dews IC, Ney PH, Cary LH, Fukumoto R, Elliott TB, Ledney GD (2012) Wound trauma alters ionizing radiation dose assessment. Cell Biosci. 11;2(1):20.
  4. Tsen SW, Wu TC, Kiang JG, Tsen KT (2012) Prospects for a novel ultrashort pulsed laser technology for pathogen inactivation. J Biomed Sci. 19(1):62.
2011
  1. Fukumoto R, Kiang JG (2011) Geldanamycin analog 17-DMAG limits apoptosis in human peripheral blood cells by inhibition of p53 activation and its interaction with heat shock protein 90 kDa after ionizing radiation. J Radiat Res. 176(3):333–345
  2. Kiang JG, Agravante NG, Smith JT, Bowman PD (2011)  17-DMAG diminishes hemorrhage-induced small intestine injury by elevating Bcl-2 protein and inhibiting iNOS pathway, TNF-alpha increase, and caspase-3 activation. Cell & Bioscience 1:21.
  3. Tsen KT, Tsen SW, Fu Q, Lindsay SM, Li Z, Cope S, Vaiana S, Kiang JG (2011) Studies of inactivation of encephalomyocarditis virus, M13 bacteriophage, and Salmonella typhimurium by using a visible femtosecond laser: Insight into the possible inactivation mechanisms. J Biomed Opt. 16:078003.
2010
  1. Carrier CA, Elliott TB, Ledney GD (2010) Real-time telemetric monitoring in whole-body (60)Co gamma-photon irradiated rhesus macaques (Macaca mulatta). J Med Primatol. 39:399–407.
  2. Daly MJ, Gaidamakova EK, Matrosova VY, Kiang JG, Fukumoto R, Lee DY, Wehr NB, Viteri GA, Berlett BS, Levine RL (2010) Small-molecule antioxidant proteome-shields in Deinococcus radiodurans. PLoS One. 5(9). pii: e12570.
  3. Gorbunov NV, Garrison BR, Kiang JG (2010)  Response of crypt paneth cells in the small intestine following total-body gamma-irradiation. Int J Immunopathol Pharmacol. 23:1111–1123.
  4. Kiang JG, Garrison BR, Gorbunov NV (2010) Radiation combined injury: DNA damage, apoptosis, and autophagy. Adaptive Medicine 2:1–10.
  5. Kiang JG, Jiao W, Cary LH, Mog SR, Elliott TB, Pellmar TC, Ledney GD (2010) Wound trauma increases radiation-induced mortality by activation of iNOS pathway and elevation of cytokine concentrations and bacterial infection. Radiat Res. 173(3):319–332.
  6. Ledney GD, Elliott TB (2010) Combined injury: factors with potential to impact radiation dose assessments. Health Phys. 98(2):145–52.
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2009
  1. Carrier CA, Elliott TB, Ledney GD. Resident bacteria in a mixed population of rhesus macaque (Macaca mulatta) monkeys: a prevalence study. A pilot study. J Med Primatology 38:397–403, 2009.
  2. Gorbunov NV, Kiang JG. Up-regulation of autophagy in small intestine Paneth cell in response to total-body γ-irradiation. J Pathol 219: 242–252, 2009.
  3. Jiao W, Kiang JG, Cary L, Elliott TB, Pellmar TC, Ledney GD. COX-2 inhibitors are contraindicated for treatment of combined injury. Radiat Res 172: 686–697, 2009.
  4. Kiang JG, Smith JA, and Agravante NG. Geldanamycin analog 17-DMAG inhibits iNOS and caspases in gamma-irradiated human T cells. Radiat Res 172: 321–330, 2009.
  5. Tsen KT, Tsen SW, Fu Q, Lindsay SM, Kibler K, Jacobs B, Wu TC, Karanam B, Jagu S, Roden RB, Hung CF, Sankey OF, Ramakrishna B, Kiang JG (2009). Photonic approach to the selective inactivation of viruses with a near-infrared subpicosecond fiber laser. J Biomed Opt. 14(6):064042.
  6. Tsen KT, Tsen SWD, Hung CF, Wu TC, Kibler K, Jacob B, Kiang JG. Selective inactivation of human immuno-deficiency virus with an ultrashort pulsed laser. Proc. of SPIE 7175: 717510-1–717510-8, 2009.
2008
  1. Atkins JL, Hammamiech R, Jett M, Gorbounov NV, Asher LV, Kiang JG. α-Defensin-4 and asymmetric dimethyl arginine (ADMA) increase in mesenteric lymph after hemorrhage in anesthetized rats. Shock 30: 411–146, 2008.
  2. Kiang JG, Kiang SC, Bowman PD. 17-DMAG inhibits hemorrhage-induced injury in small intestine and lung by inactivating caspase-3. International Proceedings of International Shock Congress K628C0171:23–27, 2008.
  3. Kiang JG, Krishnan S, Lu X, Li Y. Inhibition of inducible nitric oxide synthase protects human T cells from hypoxia-induced injury. Mol Pharmacol 73:738–747, 2008.
  4. Tsen KT, Kiang JG, Ferry DK, Lu H, Scheff WJ, Lin HW, Gwo S. Dynamics of LO phonons in InN studied by subpicosecond time-resolved Raman spectroscopy. In: Ultrafast Phenomena in Semiconductors and Nanostructure Materials XII (edited by J.J. Song, K.T. Tsen, M. Betz and A. Elezzabi), Proc. of SPIE Vol. 6892: 689206-1–689206-12, 2008.
  5. Tsen KT, Tsen S-W D, Chang C-L, Hung C-F, Wu T-C, Ramakrishna K, Mossman K, Kiang JG. Inactivation of viruses with a femtosecond laser via impulsive stimulated Raman scattering. In: Optical Interactions with Tissue and Cells XIX (edited by Steven L. Jacques, William P. Roach, Robert J. Thomas), Proc. of SPIE 6854: 68540N1–6854N10, 2008.
  6. Tsen KT, Tsen SWD, Hung CF, Wu TC, Kiang JG. Selective inactivation of human immunodeficiency virus with subpicosecond near-infrared laser pulses. J Phys Condens Matter 20:25220-1–25220-4, 2008.
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