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Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33 secreted from impaired vessels in the skin compared to fractionated irradiation

 Eun-Jung Lee  ;  Jun Won Kim  ;  Hyun Yoo  ;  Woori Kwak  ;  Won Hoon Choi  ;  Seoae Cho  ;  Yu Jeong Choi  ;  Yoon-Jin Lee  ;  Jaeho Cho 
 Biochemical and Biophysical Research Communications, Vol.464(1) : 20-26, 2015 
Journal Title
 Biochemical and Biophysical Research Communications 
Issue Date
Animals ; Antibodies/pharmacology ; Cell Movement/drug effects ; Cell Movement/radiation effects ; Chemokine CCL11/genetics ; Chemokine CCL11/metabolism ; Coculture Techniques ; Dose-Response Relationship, Radiation ; Eosinophils/drug effects ; Eosinophils/metabolism ; Eosinophils/pathology ; Eosinophils/radiation effects* ; Female ; Fibrosis ; Gene Expression ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/pathology ; Human Umbilical Vein Endothelial Cells/radiation effects* ; Humans ; Interleukin-33 ; Interleukin-4/genetics ; Interleukin-4/metabolism ; Interleukin-5/genetics ; Interleukin-5/metabolism ; Interleukins/antagonists & inhibitors ; Interleukins/genetics ; Interleukins/secretion* ; Macrophages/drug effects ; Macrophages/metabolism ; Macrophages/pathology ; Macrophages/radiation effects* ; Mice ; Radiation Dosage ; Skin/blood supply ; Skin/drug effects ; Skin/pathology* ; Skin/radiation effects* ; Swine ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism ; X-Rays
Eosinophil-mediated fibrosis ; Interleukin-33 ; Radiotherapy ; Skin injury
We have revealed in a porcine skin injury model that eosinophil recruitment was dose-dependently enhanced by a single high-dose irradiation. In this study, we investigated the underlying mechanism of eosinophil-associated skin fibrosis and the effect of high-dose-per-fraction radiation. The dorsal skin of a mini-pig was divided into two sections containing 4-cm(2) fields that were irradiated with 30 Gy in a single fraction or 5 fractions and biopsied regularly over 14 weeks. Eosinophil-related Th2 cytokines such as interleukin (IL)-4, IL-5, and C-C motif chemokine-11 (CCL11/eotaxin) were evaluated by quantitative real-time PCR. RNA-sequencing using 30 Gy-irradiated mouse skin and functional assays in a co-culture system of THP-1 and irradiated-human umbilical vein endothelial cells (HUVECs) were performed to investigate the mechanism of eosinophil-mediated radiation fibrosis. Single high-dose-per-fraction irradiation caused pronounced eosinophil accumulation, increased profibrotic factors collagen and transforming growth factor-β, enhanced production of eosinophil-related cytokines including IL-4, IL-5, CCL11, IL-13, and IL-33, and reduced vessels compared with 5-fraction irradiation. IL-33 notably increased in pig and mouse skin vessels after single high-dose irradiation of 30 Gy, as well as in irradiated HUVECs following 12 Gy. Blocking IL-33 suppressed the migration ability of THP-1 cells and cytokine secretion in a co-culture system of THP-1 cells and irradiated HUVECs. Hence, high-dose-per-fraction irradiation appears to enhance eosinophil-mediated fibrotic responses, and IL-33 may be a key molecule operating in eosinophil-mediated fibrosis in high-dose-per fraction irradiated skin.
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1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jun Won(김준원) ORCID logo https://orcid.org/0000-0003-1358-364X
Lee, Eun Jung(이은정)
Cho, Jae Ho(조재호) ORCID logo https://orcid.org/0000-0001-9966-5157
Choi, Won Hoon(최원훈)
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