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human primates (NHP, slope=1.13), characteristic of homogeneous strains and likely responsible for
variations in experimental survival. To further develop and refine mouse models of H-ARS with predictable
survival and usefulness for screening medical countermeasures (MCM), we have established an H-ARS
model in the Jackson Diversity Outbred (J: DO) strain, the most genetically diverse mice available (derived
from 160 Collaborative Cross strains). The slope of the radiation dose/lethality curve (n=407 mice) was
137
found to be 1.02, similar to that in NHP. Survival at 30 days of mice exposed to 900cGy ( Cs, 99.2-
100.1cGy/min) was 27.3% and 35.0% in consecutive experiments, suggesting the J: DO H-ARS model may
provide more predictable survival. Levofloxacin significantly increased survival at higher radiation doses
(p<0.03). The J: DO H-ARS model was validated using Neulasta, a pegylated granulocyte-colony stimulating
factor (Amgen, CA) and known radiomitigator. Survival at 30d of mice injected SQ with two doses of
1mg/kg Neulasta (days 1 and 8 post-900cGy) was 76.9%, and significantly increased compared to vehicle-
treated mice (33.3%, p<0.0001, n=52-102/grp). Significantly increased survival was also observed in
Neulasta-treated mice exposed to a higher radiation dose (948cGy). Neulasta treatment resulted in
significantly enhanced recovery of neutrophils and erythrocytes compared to vehicle-treated mice
(p≤0.02). These results confirm the efficacy of Neulasta in improving survival and peripheral blood cell
recovery in lethally irradiated J: DO mice, similar to that observed in inbred C57BL/6 mice and NHP, and
may provide an additional mouse model for screening MCM against radiation with possibly better survival
predictability. Funded by NIAID Contract HHSN272201000046C.
(PS2-48) Early life exposure to either internal contamination with 137Cs or 5 Gy total body irradiation
in 14 day old mice sensitize the lung to later life viral challenges. Jacqueline P. Williams, PhD; Carl J.
Johnston, PhD; Ravi S. Misra, PhD; Eric Hernady; Jennie Miller, MS; and Jacob N. Finkelstein, PhD
University of Rochester Medical Center, Rochester, NY
Internal contamination with radioactive material can result either for the detonation of a “dirty
bomb” packed with material or through accidental release as a result of a nuclear incident such as seen
by recent nuclear power incidents. Such exposure can lead to internal contamination and systemic
delivery of long-lived isotopes. The chronic effects of such exposure are not well characterized.
Furthermore, pulmonary responses to injury differ between the adolescent as compared to the adult,
which may affect acute and chronic responses to irradiation. Our current hypothesis suggests that
radiation during this critical period is likely to alter developmental processes resulting in long-term
consequences including altered susceptibility to secondary inflammatory challenge. Identifying these
differences would be critical in developing successful mitigation strategies for this special population.
C57BL/6J mice, 14 days of age, either received a 5 Gy TBI dose or received a single 50 uCi I.P. injection of
137Cs. Mice were examined at 12 or 26 weeks post irradiation. A second cohort of mice were intra-nasally
infected with 120 HAU of influenza A virus 26 weeks post irradiation and examined 6, 9 and 14 days post
flu inoculation. Body Weights were recorded daily. Pulmonary response was determined by histological
examination. Analysis consisted of epithelial and inflammatory markers and gene expression. Neonatal
mice demonstrated slower clearance kinetics as compared to adult mice. Furthermore significant
differences in injury were measured in neonatal mice that received systemic exposure as compared to
those mice that received external exposure. Messages encoding MCP-1 and KC were elevated at 12 weeks
in External beam irradiated mice whereas these messages were decreased 50% for controls in the
internally injected mice. These differences were even more enhanced 26 weeks post exposure. When
exposed to Influenza differential responses patterns were again measured. These results demonstrate
161 | P a g e
variations in experimental survival. To further develop and refine mouse models of H-ARS with predictable
survival and usefulness for screening medical countermeasures (MCM), we have established an H-ARS
model in the Jackson Diversity Outbred (J: DO) strain, the most genetically diverse mice available (derived
from 160 Collaborative Cross strains). The slope of the radiation dose/lethality curve (n=407 mice) was
137
found to be 1.02, similar to that in NHP. Survival at 30 days of mice exposed to 900cGy ( Cs, 99.2-
100.1cGy/min) was 27.3% and 35.0% in consecutive experiments, suggesting the J: DO H-ARS model may
provide more predictable survival. Levofloxacin significantly increased survival at higher radiation doses
(p<0.03). The J: DO H-ARS model was validated using Neulasta, a pegylated granulocyte-colony stimulating
factor (Amgen, CA) and known radiomitigator. Survival at 30d of mice injected SQ with two doses of
1mg/kg Neulasta (days 1 and 8 post-900cGy) was 76.9%, and significantly increased compared to vehicle-
treated mice (33.3%, p<0.0001, n=52-102/grp). Significantly increased survival was also observed in
Neulasta-treated mice exposed to a higher radiation dose (948cGy). Neulasta treatment resulted in
significantly enhanced recovery of neutrophils and erythrocytes compared to vehicle-treated mice
(p≤0.02). These results confirm the efficacy of Neulasta in improving survival and peripheral blood cell
recovery in lethally irradiated J: DO mice, similar to that observed in inbred C57BL/6 mice and NHP, and
may provide an additional mouse model for screening MCM against radiation with possibly better survival
predictability. Funded by NIAID Contract HHSN272201000046C.
(PS2-48) Early life exposure to either internal contamination with 137Cs or 5 Gy total body irradiation
in 14 day old mice sensitize the lung to later life viral challenges. Jacqueline P. Williams, PhD; Carl J.
Johnston, PhD; Ravi S. Misra, PhD; Eric Hernady; Jennie Miller, MS; and Jacob N. Finkelstein, PhD
University of Rochester Medical Center, Rochester, NY
Internal contamination with radioactive material can result either for the detonation of a “dirty
bomb” packed with material or through accidental release as a result of a nuclear incident such as seen
by recent nuclear power incidents. Such exposure can lead to internal contamination and systemic
delivery of long-lived isotopes. The chronic effects of such exposure are not well characterized.
Furthermore, pulmonary responses to injury differ between the adolescent as compared to the adult,
which may affect acute and chronic responses to irradiation. Our current hypothesis suggests that
radiation during this critical period is likely to alter developmental processes resulting in long-term
consequences including altered susceptibility to secondary inflammatory challenge. Identifying these
differences would be critical in developing successful mitigation strategies for this special population.
C57BL/6J mice, 14 days of age, either received a 5 Gy TBI dose or received a single 50 uCi I.P. injection of
137Cs. Mice were examined at 12 or 26 weeks post irradiation. A second cohort of mice were intra-nasally
infected with 120 HAU of influenza A virus 26 weeks post irradiation and examined 6, 9 and 14 days post
flu inoculation. Body Weights were recorded daily. Pulmonary response was determined by histological
examination. Analysis consisted of epithelial and inflammatory markers and gene expression. Neonatal
mice demonstrated slower clearance kinetics as compared to adult mice. Furthermore significant
differences in injury were measured in neonatal mice that received systemic exposure as compared to
those mice that received external exposure. Messages encoding MCP-1 and KC were elevated at 12 weeks
in External beam irradiated mice whereas these messages were decreased 50% for controls in the
internally injected mice. These differences were even more enhanced 26 weeks post exposure. When
exposed to Influenza differential responses patterns were again measured. These results demonstrate
161 | P a g e
