Page 276 - 2014 Printable Abstract Book
P. 276
(PS4-70) A biological model of mortality risk from early permeability changes after radiation and burn
combined injury. Daniela L. Stricklin, PhD and Darren Oldson, PhD, Applied Research Associates,
Arlington, VA
Historical data indicates that the risk of mortality after radiation injury increases dramatically
when combined with other insults. Furthermore, presentation of severe clinical symptoms and mortality
occur sooner in combined injuries. To date, most mathematical modeling efforts in this area have been
limited to simple empirical comparisons of outcome. In an effort to understand the increased risk and
abbreviated onset of illness after radiation and burn injury, physiologically-based models of mortality have
been constructed. A model for one of the earliest pathophysiological mechanisms encountered in severe
exposures, circulatory shock, has been examined. The model is based on changes in localized and systemic
microvascular fluid exchange after thermal injury which can be related to global threat of circulatory
shock. The impact of radiation-induced permeability changes on the parameters of the microvascular
exchange model have been investigated. Radiation-specific perturbation parameters were developed and
integrated into the model. Plasma volume depletion was mapped to the predicted risk of mortality for the
combined insults. Simulations of the combined insults help predict the increased mortality and shortened
time to mortality observed after combined injury. Development of biological models that describe the
pathophysiological mechanisms after radiation and burn injury enables improved estimates of mortality,
provides estimates of clinical parameters resulting from the injuries, and gives an indication of the patient
flow that can be anticipated from combined injuries. Collectively, this information can help inform public
health and medical response planners and may be used to suggest focus areas for experimental research.
(PS4-71) Tumor microenvironment promotes radioresistance of lung cancer cells through activation of
Nrf2-EGFR axis. Jiyeon Ahn; Saelooom Lee; A-rang Son; and Jie-Young Song, Korea Institute of Radiological
& Medical Sciences (KIRAMS), Seoul, Korea, Republic of
Radiotherapy (RT) is an effective cancer treatment modality for solid tumors that exerts DNA
damage and its cytotoxicity by generating reactive oxygen spices (ROS). However, one of major obstacles
in radiotherapy is tumor microenvironment which confers resistance to ROS-mediated cell death. To
elucidate the effect of redox system of cancer cells on cell proliferation and radioresistance in the
presence of TGF-β under hypoxia-reoxygenation condition for closely mimicking in vivo tumor
microenvironment, human non-small cell lung cancer (NSCLC) A549 cells were treated with 1ng/ml TGF-
β and incubated with hypoxia for 2 h followed by reoxygenation. The combination treatment of TGF-β and
hypoxia significantly induced protein level of Nrf2 which is a redox-sensitive transcription factor and its
downstream target proteins HO-1 and Srx-1 compared with TGF-β or hypoxia alone. The mRNA level of
HO-1 and Srx-1 was also increased in combined treatment but that of Nrf2 was not changed. The
proliferation of A549 cells with treatment of TGF-β under hypoxia increased compared vehicle, and
exhibited resistance to ionizing radiation (IR). However, knockdown of Nrf2 with siRNA led to an increase
of IR-induced cell death than vehicle under these circumstances, suggesting that Nrf2 contributes to
radioresistance under tumor microenvironment. Since EGFR is abundantly expressed in NSCLC cells, we
examined expression and phosphorylation of EGFR protein. Phosphorylation of EGFR, but not the protein
level, was significantly induced in combination treatment of TGF-β and hypoxia compared with each
treatment alone. Interestingly, Nrf2 knockdown suppressed the combined treatment-induced
phosphorylation of EGFR. Inhibition of EGFR with AG1478 suppressed induction of Nrf2 in the combined
274 | P a g e
combined injury. Daniela L. Stricklin, PhD and Darren Oldson, PhD, Applied Research Associates,
Arlington, VA
Historical data indicates that the risk of mortality after radiation injury increases dramatically
when combined with other insults. Furthermore, presentation of severe clinical symptoms and mortality
occur sooner in combined injuries. To date, most mathematical modeling efforts in this area have been
limited to simple empirical comparisons of outcome. In an effort to understand the increased risk and
abbreviated onset of illness after radiation and burn injury, physiologically-based models of mortality have
been constructed. A model for one of the earliest pathophysiological mechanisms encountered in severe
exposures, circulatory shock, has been examined. The model is based on changes in localized and systemic
microvascular fluid exchange after thermal injury which can be related to global threat of circulatory
shock. The impact of radiation-induced permeability changes on the parameters of the microvascular
exchange model have been investigated. Radiation-specific perturbation parameters were developed and
integrated into the model. Plasma volume depletion was mapped to the predicted risk of mortality for the
combined insults. Simulations of the combined insults help predict the increased mortality and shortened
time to mortality observed after combined injury. Development of biological models that describe the
pathophysiological mechanisms after radiation and burn injury enables improved estimates of mortality,
provides estimates of clinical parameters resulting from the injuries, and gives an indication of the patient
flow that can be anticipated from combined injuries. Collectively, this information can help inform public
health and medical response planners and may be used to suggest focus areas for experimental research.
(PS4-71) Tumor microenvironment promotes radioresistance of lung cancer cells through activation of
Nrf2-EGFR axis. Jiyeon Ahn; Saelooom Lee; A-rang Son; and Jie-Young Song, Korea Institute of Radiological
& Medical Sciences (KIRAMS), Seoul, Korea, Republic of
Radiotherapy (RT) is an effective cancer treatment modality for solid tumors that exerts DNA
damage and its cytotoxicity by generating reactive oxygen spices (ROS). However, one of major obstacles
in radiotherapy is tumor microenvironment which confers resistance to ROS-mediated cell death. To
elucidate the effect of redox system of cancer cells on cell proliferation and radioresistance in the
presence of TGF-β under hypoxia-reoxygenation condition for closely mimicking in vivo tumor
microenvironment, human non-small cell lung cancer (NSCLC) A549 cells were treated with 1ng/ml TGF-
β and incubated with hypoxia for 2 h followed by reoxygenation. The combination treatment of TGF-β and
hypoxia significantly induced protein level of Nrf2 which is a redox-sensitive transcription factor and its
downstream target proteins HO-1 and Srx-1 compared with TGF-β or hypoxia alone. The mRNA level of
HO-1 and Srx-1 was also increased in combined treatment but that of Nrf2 was not changed. The
proliferation of A549 cells with treatment of TGF-β under hypoxia increased compared vehicle, and
exhibited resistance to ionizing radiation (IR). However, knockdown of Nrf2 with siRNA led to an increase
of IR-induced cell death than vehicle under these circumstances, suggesting that Nrf2 contributes to
radioresistance under tumor microenvironment. Since EGFR is abundantly expressed in NSCLC cells, we
examined expression and phosphorylation of EGFR protein. Phosphorylation of EGFR, but not the protein
level, was significantly induced in combination treatment of TGF-β and hypoxia compared with each
treatment alone. Interestingly, Nrf2 knockdown suppressed the combined treatment-induced
phosphorylation of EGFR. Inhibition of EGFR with AG1478 suppressed induction of Nrf2 in the combined
274 | P a g e
