Page 284 - 2014 Printable Abstract Book
P. 284
(PS4-85) Ghrelin therapy improves survival after whole-body ionizing irradiation combined with
wound or burn. Juliann G. Kiang, PhD; Min Zhai, MD; Pei-Jyun Liao, MS; David L. Bolduc, PhD; Thomas B.
Elliott, PhD; and Nikolai V. Gorbunov, PhD, Armed Forces Radiobiology Research Institute, Bethesda, MD
Exposure to ionizing radiation alone (radiation injury, RI) or combined with traumatic tissue injury
(radiation combined injury, CI) is a crucial life-threatening factor in nuclear and radiological accidents.
Radiation injuries occur at the molecular, cellular, tissue, and system levels. In our laboratory, we found
60
that B6D2F1/J female mice exposed to Co-γ-photon radiation (9.5 Gy, 0.4 Gy/min, bilateral) followed by
15% total-body-surface-area skin wounds (R-W CI) or burns R-B CI) experienced an increment of ≥18%
higher mortality over a 30-day observation period compared to irradiation alone. CI was accompanied by
severe cytopenia, thrombopenia, erythropenia, and anemia. At the 30th day post-injury, numbers of
neutrophils, lymphocytes, and platelets still remained very low in surviving RI and CI mice. In contrast,
their RBC, hemoglobin, and hematocrit were similar to pre-irradiation levels. Comparing surviving CI and
RI mice, only RI induced splenomegaly. Both RI and CI resulted in bone-marrow cell depletion. Hunger
simulates release of the 28-amino-acid-peptide ghrelin from the stomach. In R-W CI mice, ghrelin
treatment (113 μg/kg, i.v., +1d, +2d, +3d once daily) significantly increased 30-day survival and mitigated
CI-induced body-weight loss, accelerated wound healing, and increased hematocrit. In R-B CI mice, ghrelin
treatment significantly increased 30-day survival and numbers of neutrophils, lymphocytes, monocytes,
basophils, and platelets, inhibited splenomegaly, and ameliorated bone-marrow cell depletion. The
results suggest that ghrelin effectively sustained animal survival by mitigating radiation-induced
cytopenia, and thrombopenia and alleviating bone-marrow injury. (The work was supported by NIH/NIAID
YI-AI-5045-04. The views, opinions, and findings contained in this presentation do not reflect official policy
or positions of the US Department of Defense or the US Government.)
(PS4-86) Hydroxytyrosol inhibits chemokine C-C motif ligand 5 mediated aged quiescent fibroblast
1
2
induced stimulation of breast cancer cell proliferation. Ehab H. Sarsour, PhD ; Monali Goswami, BS ;
1
1
1
Amanda L. Kalen, BS ; John T. Lafin, BS ; and Prabhat C. Goswami, PhD, The University of Iowa, Iowa city,
2
1
IA and Integrated DNA Technologies, Coralville, IA
Cancer is an age-associated disease. Although the mechanisms of Age-associated increase in
cancer incidence are not completely understood, it is believed that the tumor stromal environment
significantly influences epithelial malignancy and therapy outcomes. Fibroblast is a major cell type in the
stroma and under normal conditions fibroblasts reside in the quiescent state. We have shown previously
that quiescent fibroblasts lose their proliferative capacity as they age and we defined this mode of cellular
aging as chronological life span. Using conditioned media and co-culture experiments, results show that
normal human fibroblasts (NHFs) nearing the end of their chronological lifespan stimulate the
proliferation of MB231 and MCF7 human breast epithelial cancer cells. The expression of chemokine C-C
motif ligand 5 (CCL5) was found to be approximately 8-fold higher in old compared to young NHFs. NHF
age- associated increase in CCL5 activated the ERK1/2-cyclin D1 pro-proliferative pathway in MB231 cells
and enhanced MB231 proliferation. Conditioned media treated with anti-CCL5 antibody suppressed the
activation of the ERK1/2-cyclin D1 pathway and proliferation of MB231 cells Hydroxytyrosol, a dietary
polyphenol, inhibited CCL5 accumulation in aging NHFs, and suppressed NHFs ability to activate the
ERK1/2-cyclin D1 pathway in MB231 cells and their proliferation. Interestingly, 4 Gy irradiated MB231 cells
cultured in conditioned media collected from aging-NHFs showed a doubling time of 23 hours compared
282 | P a g e
wound or burn. Juliann G. Kiang, PhD; Min Zhai, MD; Pei-Jyun Liao, MS; David L. Bolduc, PhD; Thomas B.
Elliott, PhD; and Nikolai V. Gorbunov, PhD, Armed Forces Radiobiology Research Institute, Bethesda, MD
Exposure to ionizing radiation alone (radiation injury, RI) or combined with traumatic tissue injury
(radiation combined injury, CI) is a crucial life-threatening factor in nuclear and radiological accidents.
Radiation injuries occur at the molecular, cellular, tissue, and system levels. In our laboratory, we found
60
that B6D2F1/J female mice exposed to Co-γ-photon radiation (9.5 Gy, 0.4 Gy/min, bilateral) followed by
15% total-body-surface-area skin wounds (R-W CI) or burns R-B CI) experienced an increment of ≥18%
higher mortality over a 30-day observation period compared to irradiation alone. CI was accompanied by
severe cytopenia, thrombopenia, erythropenia, and anemia. At the 30th day post-injury, numbers of
neutrophils, lymphocytes, and platelets still remained very low in surviving RI and CI mice. In contrast,
their RBC, hemoglobin, and hematocrit were similar to pre-irradiation levels. Comparing surviving CI and
RI mice, only RI induced splenomegaly. Both RI and CI resulted in bone-marrow cell depletion. Hunger
simulates release of the 28-amino-acid-peptide ghrelin from the stomach. In R-W CI mice, ghrelin
treatment (113 μg/kg, i.v., +1d, +2d, +3d once daily) significantly increased 30-day survival and mitigated
CI-induced body-weight loss, accelerated wound healing, and increased hematocrit. In R-B CI mice, ghrelin
treatment significantly increased 30-day survival and numbers of neutrophils, lymphocytes, monocytes,
basophils, and platelets, inhibited splenomegaly, and ameliorated bone-marrow cell depletion. The
results suggest that ghrelin effectively sustained animal survival by mitigating radiation-induced
cytopenia, and thrombopenia and alleviating bone-marrow injury. (The work was supported by NIH/NIAID
YI-AI-5045-04. The views, opinions, and findings contained in this presentation do not reflect official policy
or positions of the US Department of Defense or the US Government.)
(PS4-86) Hydroxytyrosol inhibits chemokine C-C motif ligand 5 mediated aged quiescent fibroblast
1
2
induced stimulation of breast cancer cell proliferation. Ehab H. Sarsour, PhD ; Monali Goswami, BS ;
1
1
1
Amanda L. Kalen, BS ; John T. Lafin, BS ; and Prabhat C. Goswami, PhD, The University of Iowa, Iowa city,
2
1
IA and Integrated DNA Technologies, Coralville, IA
Cancer is an age-associated disease. Although the mechanisms of Age-associated increase in
cancer incidence are not completely understood, it is believed that the tumor stromal environment
significantly influences epithelial malignancy and therapy outcomes. Fibroblast is a major cell type in the
stroma and under normal conditions fibroblasts reside in the quiescent state. We have shown previously
that quiescent fibroblasts lose their proliferative capacity as they age and we defined this mode of cellular
aging as chronological life span. Using conditioned media and co-culture experiments, results show that
normal human fibroblasts (NHFs) nearing the end of their chronological lifespan stimulate the
proliferation of MB231 and MCF7 human breast epithelial cancer cells. The expression of chemokine C-C
motif ligand 5 (CCL5) was found to be approximately 8-fold higher in old compared to young NHFs. NHF
age- associated increase in CCL5 activated the ERK1/2-cyclin D1 pro-proliferative pathway in MB231 cells
and enhanced MB231 proliferation. Conditioned media treated with anti-CCL5 antibody suppressed the
activation of the ERK1/2-cyclin D1 pathway and proliferation of MB231 cells Hydroxytyrosol, a dietary
polyphenol, inhibited CCL5 accumulation in aging NHFs, and suppressed NHFs ability to activate the
ERK1/2-cyclin D1 pathway in MB231 cells and their proliferation. Interestingly, 4 Gy irradiated MB231 cells
cultured in conditioned media collected from aging-NHFs showed a doubling time of 23 hours compared
282 | P a g e
