S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
Radiation-induced esophagitis in vivo and in vitro reveals that epidermal growth factor (EGF) is a potential candidate for therapeutic intervention strategy
방사선유발 식도염의 in vivo, in vitro 모델에서 표피성장인자(epidermal growth factor)의 효능 연구
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과 방사선종양학과, 2016. 8. 김학재.
- Purpose: To establish and characterize radiation-induced esophagitis (RIE) in vivo and in vitro.
Materials and Methods: Fractionated thoracic irradiation at 0, 8, 12, or 15 Gy was given daily for 5 days to Balb/c or C57Bl/6 mice. Changes in the body weight gain and daily food intake were assessed. At the end of the study, we harvested the esophagus and examined: (i) histology by H&E staining
(ii) immune cell infiltration and apoptosis by Fluorescent activated cell sorting (FACS)
(iii) gene expression changes by qRT-PCR. Het-1A human esophageal epithelial cells were irradiated at 6 Gy, treated with recombinant human growth factors, and examined for gene expression changes, apoptosis, proliferation, and signal transduction pathways.
Results: We observed that irradiation at 12 Gy or 15 Gy per fraction produced a significant body weight reduction and decreased food intake in Balb/c mice, but not so much in C57Bl/6 mice. Further analyses of Balb/c mice irradiated at 12 Gy/fraction revealed an attenuated epithelium, inflamed mucosa, and increased number of infiltrating CD4+ helper T cells and apoptotic cells. Moreover we found that expressions of tissue inhibitor for metalloproteinase-1, plasminogen activator inhibitor-1, granulocyte macrophage-colony stimulating factor, vascular endothelial growth factor, and stromal-derived factor-1 were increased while epidermal growth factor (Egf) was decreased. Irradiated Het-1A cells similarly showed a significant decrease in EGF and connective tissue growth factor (CTGF) expression. Treatment of EGF but not CTGF partially protected Het-1A cells from radiation-induced apoptosis and revealed phosphorylation of EGFR, AKT and ERK signaling pathways.
Conclusions: We established a mouse model of RIE in Balb/c mice with 12 Gy × 5 fractions, which exhibited reduced body weight gain, food intake, and histopathologic features similar to human esophagitis. Decreased EGF expression in the irradiated esophagus suggests that EGF may be a potential therapeutic intervention strategy to treat RIE.