Page 166 - 2014 Printable Abstract Book
P. 166
critical for the repair of intestinal mucosa, but their role in the prolonged GI syndrome in unclear. The aim
of this study was to determine the factors that contribute to survival in the prolonged GI syndrome that
follows the acute radiation syndrome (GI-ARS) in mice. Methods: Cohorts of male CBA/Ca mice aged 10-
12 wks were irradiated at staggered times with 13 Gy PBI/BM5 using an X-ray radiation source at an
exposure rate of 0.812Gy/minute, 300kV, 10mA. Groups of irradiated mice and age-matched controls
were euthanized at intervals between 6-180 days post irradiation (d PI). Results: Survival past day 20 was
less than 50% in any irradiated cohort. Weight loss occurred in the first week and again at 18d reflecting
progression through GI-ARS and hematopoietic syndromes. White blood cell counts were normalized by
60d PI. Transepithelial electrical resistance (TEER), an index of small intestinal permeability, was
decreased (enhanced permeability) significantly between 6 and 60d PI. TEER decreased with age such that
after 90d PI, TEER in irradiated mice was no different from age-matched controls. Inducible nitric oxide
(NOS2) is produced by M1 macrophages that are critical for host defense against pathogens and key to
controlling the tumor microenvironment. NOS2 expression was upregulated significantly in both the small
intestine and colon at all-time points post 13Gy PBI/BM5. MUC2, the primary colonic mucin, and MUC5AC,
a mucin associated with colonic cancer, were upregulated at 90-180d PI. Lgr5 expression in the small
intestine is correlated with CBC number and was downregulated significantly by 69% at 6d, reached a
nadir of 88% at day 30-60d, and recovered to ~ 50% of levels in age matched controls by 180d. Thus, Lgr5+
crypt basal cells (CBC) exhibit marked radiosensitivity in the prolonged GI syndrome. These data show that
prolonged GI syndrome features mucosal barrier dysfunction associated with persistent inflammation,
altered mucin production, and impaired stem cell recovery. Supported by HHSN272201000046C.
(PS2-54) Development of a Large Animal Model of h-ARS in Gottingen Minipigs under Minimal
Supportive Care: Natural History and Biomarker Results for Radiation Injury from Multiple Institutions
using a Harmonized Model. Demonstration of Reproducibility for Regulatory Acceptance. John L. Esker,
1
2
1
1
1
PhD ; Brian Moyer ; Robert Raulli, PhD ; Marcy Grace, PhD ; Waylon Weber, PhD ; Melanie Doyle-Eisele,
2
3
2
PhD ; Dunstana Melo, PhD ; Ray Guilmette, PhD ; Karla Thrall, PhD, DABT ; Maria Moroni, Ph.,D. ; Amelia
2
4
5
5
5
1
Bartholomew, MD, MPH, FACS ; Matt Lindeblad ; and Alex Lyubimov, PhD, BARDA, Washington, DC ;
2
Lovelace Respiratory Research Institute, Albuquerque, NM ; Pacific Northwest National Laboratory,
3
4
Richland, WA ; Armed Forces Radiobiology Research Institute, Bethesda, MD ; and University of Illinois at
5
Chicago, Chicago, IL
PURPOSE: Models for hematopoietic acute radiation syndrome (h-ARS) have used the murine,
canine or non-human primate (NHP) species. A minipig (MP) is an attractive alternative large animal model
for radiation specific sub-syndromes. The Biomedical Advanced Research and Development Authority
(BARDA) is funding studies at several institutions to establish a robust MP model for ultimate use in
developing medical countermeasures (MCMs) and submission to the FDA under the Animal Model
Qualification Program. METHODS: Institutions are working with BARDA to develop the MP model for h-
ARS in the in-field, early treatment time period for a mass casualty setting after a nuclear detonation. Both
60
LINAC and Co radiation sources are used for total body irradiation (TBI) doses in the range of 1.6-2.5 Gy
with bilateral irradiation at 0.5-0.8 Gy/min. Animals were fitted with vascular access ports (VAPs) and
given no or minimal supportive care. Clinical signs of h-ARS are monitored. Blood samples are collected
prior to irradiation (baseline), and at predetermined intervals post-irradiation for assessment of
biomarkers. RESULTS: The LD50s values across the institutions lie between 1.8 and 2.1 Gy. A dose
modification factor of about 1.1 was observed with inclusion of oral fluids and antibiotics vs. no supportive
164 | P a g e
of this study was to determine the factors that contribute to survival in the prolonged GI syndrome that
follows the acute radiation syndrome (GI-ARS) in mice. Methods: Cohorts of male CBA/Ca mice aged 10-
12 wks were irradiated at staggered times with 13 Gy PBI/BM5 using an X-ray radiation source at an
exposure rate of 0.812Gy/minute, 300kV, 10mA. Groups of irradiated mice and age-matched controls
were euthanized at intervals between 6-180 days post irradiation (d PI). Results: Survival past day 20 was
less than 50% in any irradiated cohort. Weight loss occurred in the first week and again at 18d reflecting
progression through GI-ARS and hematopoietic syndromes. White blood cell counts were normalized by
60d PI. Transepithelial electrical resistance (TEER), an index of small intestinal permeability, was
decreased (enhanced permeability) significantly between 6 and 60d PI. TEER decreased with age such that
after 90d PI, TEER in irradiated mice was no different from age-matched controls. Inducible nitric oxide
(NOS2) is produced by M1 macrophages that are critical for host defense against pathogens and key to
controlling the tumor microenvironment. NOS2 expression was upregulated significantly in both the small
intestine and colon at all-time points post 13Gy PBI/BM5. MUC2, the primary colonic mucin, and MUC5AC,
a mucin associated with colonic cancer, were upregulated at 90-180d PI. Lgr5 expression in the small
intestine is correlated with CBC number and was downregulated significantly by 69% at 6d, reached a
nadir of 88% at day 30-60d, and recovered to ~ 50% of levels in age matched controls by 180d. Thus, Lgr5+
crypt basal cells (CBC) exhibit marked radiosensitivity in the prolonged GI syndrome. These data show that
prolonged GI syndrome features mucosal barrier dysfunction associated with persistent inflammation,
altered mucin production, and impaired stem cell recovery. Supported by HHSN272201000046C.
(PS2-54) Development of a Large Animal Model of h-ARS in Gottingen Minipigs under Minimal
Supportive Care: Natural History and Biomarker Results for Radiation Injury from Multiple Institutions
using a Harmonized Model. Demonstration of Reproducibility for Regulatory Acceptance. John L. Esker,
1
2
1
1
1
PhD ; Brian Moyer ; Robert Raulli, PhD ; Marcy Grace, PhD ; Waylon Weber, PhD ; Melanie Doyle-Eisele,
2
3
2
PhD ; Dunstana Melo, PhD ; Ray Guilmette, PhD ; Karla Thrall, PhD, DABT ; Maria Moroni, Ph.,D. ; Amelia
2
4
5
5
5
1
Bartholomew, MD, MPH, FACS ; Matt Lindeblad ; and Alex Lyubimov, PhD, BARDA, Washington, DC ;
2
Lovelace Respiratory Research Institute, Albuquerque, NM ; Pacific Northwest National Laboratory,
3
4
Richland, WA ; Armed Forces Radiobiology Research Institute, Bethesda, MD ; and University of Illinois at
5
Chicago, Chicago, IL
PURPOSE: Models for hematopoietic acute radiation syndrome (h-ARS) have used the murine,
canine or non-human primate (NHP) species. A minipig (MP) is an attractive alternative large animal model
for radiation specific sub-syndromes. The Biomedical Advanced Research and Development Authority
(BARDA) is funding studies at several institutions to establish a robust MP model for ultimate use in
developing medical countermeasures (MCMs) and submission to the FDA under the Animal Model
Qualification Program. METHODS: Institutions are working with BARDA to develop the MP model for h-
ARS in the in-field, early treatment time period for a mass casualty setting after a nuclear detonation. Both
60
LINAC and Co radiation sources are used for total body irradiation (TBI) doses in the range of 1.6-2.5 Gy
with bilateral irradiation at 0.5-0.8 Gy/min. Animals were fitted with vascular access ports (VAPs) and
given no or minimal supportive care. Clinical signs of h-ARS are monitored. Blood samples are collected
prior to irradiation (baseline), and at predetermined intervals post-irradiation for assessment of
biomarkers. RESULTS: The LD50s values across the institutions lie between 1.8 and 2.1 Gy. A dose
modification factor of about 1.1 was observed with inclusion of oral fluids and antibiotics vs. no supportive
164 | P a g e
