Page 31 - 2014 Printable Abstract Book
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the long-term damaging effects of radiation on articular cartilage. In vitro studies have determined that
radiation can induce an osteoarthritic phenotype. An early and active loss of glycosaminoglycans (GAGs)
from cartilage via increased matrix metalloproteinase (MMP) production is observed after irradiation. This
is coupled with reduced formation of GAGs. The early loss of cartilage occurs with deterioration of
biomechanical properties. Early (Days 2 and 14) and long-term (Day 40) in vitro data suggests radiation-
induced articular cartilage damage may result from chondrocyte hypertrophy. We measured, i] increased
expression of collagen X and MMP-13, ii] decreased expression of collagen II and aggrecan, and iii]
increased alkaline phosphatase (ALP) activity. These long-term changes in the pattern of gene expression
and ALP activity may suppress cartilage formation, degrade cartilage, and cause cartilage calcification. To
examine if TBI has long-term effects on cartilage, we exposed skeletally immature 14 week old rats to 1,
3, and 7 Gy TBI and used nanoCT, 7T MRI, and histology to characterize knee joint degradation at a
skeletally mature 53 weeks of age compared to 0 Gy controls. Discrete calcified lesions in the articular
cartilage were only seen in the irradiated knees. T2 values from the weight-bearing tibial cartilage-
cartilage contact areas were lower than 0 Gy controls after all doses, suggesting hypertrophy and altered
collagen composition. Histologic analysis revealed cartilage degradation occurred in a dose-dependent
manner. Collectively, these results are consistent with the clinical findings of early and persistent
alterations in chondrocyte and cartilage tissue that likely contribute to joint degeneration in the irradiated
survivors of childhood cancers.
(S103) Radiation-induced breakdown of the cutaneous physical and immunological barrier: Functional
consequences and possible mitigation. Scott A. Gerber; Julie L. Ryan; Margaret L. Barlow; Ryan J.
Cummings; Alice P. Pentland; Constantine G. Haidaris; and Edith M. Lord, University of Rochester Medical
Center, Rochester, NY
The United States continues to be a prime target for attack by terrorist organizations in which
nuclear detonation or dispersal of radiological material are legitimate threats. These types of attacks could
result in significant toxicities as a result of radiation injury to particular organ systems. One of these
organs, the cutaneous system, which forms both a physical and immunological barrier to the surrounding
environment, is particularly sensitive to ionizing radiation. To monitor cutaneous radiation injury, we
developed a murine model that recapitulates extensive, but potentially survivable exposure to ionizing
radiation, consisting of a total body dose of 6 Gy combined with superficial cutaneous β-irradiation
(emulating fallout). Combined radiation injury resulted in a breakdown in skin integrity as measured by
transepidermal water loss, size of β-burn lesion, and loss of surveillant cutaneous dendritic cells. We
hypothesized that a radiation-induced disruption in both the physical and immunological barrier would
leave the host vulnerable to cutaneous pathogen attack. Indeed, mice exposed to radiation and
challenged with the opportunistic pathogen Candida albicans presented with more severe localized
infection along with systemic dissemination to the kidney when compared to unirradiated controls. We
explored the use of medical countermeasures that may mitigate the damaging effects of cutaneous
radiation exposure. Interestingly, administration of interleukin-12 (IL-12) 48 hours after combined injury
reversed the deleterious effects of radiation and significantly improved skin integrity. Furthermore, IL-12
therapy lessened the severity of cutaneous and systemic C. albicans infection. Our data further define the
effects of radiation injury on the skin and suggest the further development of IL-12 as a potential mitigator
of radiation-induced cutaneous injury.
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radiation can induce an osteoarthritic phenotype. An early and active loss of glycosaminoglycans (GAGs)
from cartilage via increased matrix metalloproteinase (MMP) production is observed after irradiation. This
is coupled with reduced formation of GAGs. The early loss of cartilage occurs with deterioration of
biomechanical properties. Early (Days 2 and 14) and long-term (Day 40) in vitro data suggests radiation-
induced articular cartilage damage may result from chondrocyte hypertrophy. We measured, i] increased
expression of collagen X and MMP-13, ii] decreased expression of collagen II and aggrecan, and iii]
increased alkaline phosphatase (ALP) activity. These long-term changes in the pattern of gene expression
and ALP activity may suppress cartilage formation, degrade cartilage, and cause cartilage calcification. To
examine if TBI has long-term effects on cartilage, we exposed skeletally immature 14 week old rats to 1,
3, and 7 Gy TBI and used nanoCT, 7T MRI, and histology to characterize knee joint degradation at a
skeletally mature 53 weeks of age compared to 0 Gy controls. Discrete calcified lesions in the articular
cartilage were only seen in the irradiated knees. T2 values from the weight-bearing tibial cartilage-
cartilage contact areas were lower than 0 Gy controls after all doses, suggesting hypertrophy and altered
collagen composition. Histologic analysis revealed cartilage degradation occurred in a dose-dependent
manner. Collectively, these results are consistent with the clinical findings of early and persistent
alterations in chondrocyte and cartilage tissue that likely contribute to joint degeneration in the irradiated
survivors of childhood cancers.
(S103) Radiation-induced breakdown of the cutaneous physical and immunological barrier: Functional
consequences and possible mitigation. Scott A. Gerber; Julie L. Ryan; Margaret L. Barlow; Ryan J.
Cummings; Alice P. Pentland; Constantine G. Haidaris; and Edith M. Lord, University of Rochester Medical
Center, Rochester, NY
The United States continues to be a prime target for attack by terrorist organizations in which
nuclear detonation or dispersal of radiological material are legitimate threats. These types of attacks could
result in significant toxicities as a result of radiation injury to particular organ systems. One of these
organs, the cutaneous system, which forms both a physical and immunological barrier to the surrounding
environment, is particularly sensitive to ionizing radiation. To monitor cutaneous radiation injury, we
developed a murine model that recapitulates extensive, but potentially survivable exposure to ionizing
radiation, consisting of a total body dose of 6 Gy combined with superficial cutaneous β-irradiation
(emulating fallout). Combined radiation injury resulted in a breakdown in skin integrity as measured by
transepidermal water loss, size of β-burn lesion, and loss of surveillant cutaneous dendritic cells. We
hypothesized that a radiation-induced disruption in both the physical and immunological barrier would
leave the host vulnerable to cutaneous pathogen attack. Indeed, mice exposed to radiation and
challenged with the opportunistic pathogen Candida albicans presented with more severe localized
infection along with systemic dissemination to the kidney when compared to unirradiated controls. We
explored the use of medical countermeasures that may mitigate the damaging effects of cutaneous
radiation exposure. Interestingly, administration of interleukin-12 (IL-12) 48 hours after combined injury
reversed the deleterious effects of radiation and significantly improved skin integrity. Furthermore, IL-12
therapy lessened the severity of cutaneous and systemic C. albicans infection. Our data further define the
effects of radiation injury on the skin and suggest the further development of IL-12 as a potential mitigator
of radiation-induced cutaneous injury.
29 | P a g e
