Inflammation as well as angiogenesis may participate in the pathophysiology of brain radiation necrosis

Radiation necrosis (RN) after intensive radiation therapy is a serious problem. Using human RN specimens, we recently proved that leaky angiogenesis is a major cause of brain edema in RN. In the present study, we investigated the same specimens to speculate on inflammation's effect on the patho...

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Bibliographic Details
Published in:Journal of radiation research 2014-07, Vol.55 (4), p.803-811
Main Authors: Yoritsune, Erina, Furuse, Motomasa, Kuwabara, Hiroko, Miyata, Tomo, Nonoguchi, Naosuke, Kawabata, Shinji, Hayasaki, Hana, Kuroiwa, Toshihiko, Ono, Koji, Shibayama, Yuro, Miyatake, Shin-Ichi
Format: Article
Language:English
Subjects:
Adult
Aged
Analysis
Brain
Brain Injuries - etiology
Brain Injuries - pathology
Brain Injuries - physiopathology
Brain Neoplasms - radiotherapy
Chemokines - metabolism
Control
Cytokines
Edema
Female
Human
Humans
Immunohistochemistry
Infiltration
Inflammation
Inflammation - etiology
Inflammation - pathology
Inflammation - physiopathology
Male
Middle Aged
Necrosis
Neovascularization, Pathologic - etiology
Oncology
Radiation (Physics)
Radiation Injuries - etiology
Radiation Injuries - pathology
Radiation Injuries - physiopathology
Radiotherapy
Radiotherapy - adverse effects
Receptors
Receptors, Chemokine - metabolism
Staining
Tumor necrosis factor
Vascular endothelial growth factor
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Summary:Radiation necrosis (RN) after intensive radiation therapy is a serious problem. Using human RN specimens, we recently proved that leaky angiogenesis is a major cause of brain edema in RN. In the present study, we investigated the same specimens to speculate on inflammation's effect on the pathophysiology of RN. Surgical specimens of symptomatic RN in the brain were retrospectively reviewed by histological and immunohistochemical analyses using hematoxylin and eosin (H&E) staining as well as immunohistochemical staining for VEGF, HIF-1α, CXCL12, CXCR4, GFAP, CD68, hGLUT5, CD45, IL-1α, IL-6 TNF-α and NF-kB. H&E staining demonstrated marked angiogenesis and cell infiltration in the perinecrotic area. The most prominent vasculature was identified as thin-walled leaky angiogenesis, i.e. telangiectasis surrounded by prominent interstitial edema. Two major cell phenotypes infiltrated the perinecrotic area: GFAP-positive reactive astrocytes and CD68/hGLUT5-positive cells (mainly microglias). Immunohistochemistry revealed that CD68/hGLUT5-positive cells and GFAP-positive cells expressed HIF-1α and VEGF, respectively. GFAP-positive cells expressed chemokine CXCL12, and CD68/hGLUT5-positive cells expressed receptor CXCR4. The CD68/hGLUT5-positive cells expressed pro-inflammatory cytokines IL-1α, IL-6 and TNF-α in the perinecrotic area. VEGF caused leaky angiogenesis followed by perilesional edema in RN. GFAP-positive cells expressing CXCL12 might attract CXCR4-expressing CD68/hGLUT5-positive cells into the perinecrotic area. These accumulated CD68/hGLUT5-positive cells expressing pro-inflammatory cytokines seemed to aggravate the RN edema. Both angiogenesis and inflammation might be caused by the regulation of HIF-1α, which is well known as a transactivator of VEGF and of the CXCL12/CXCR4 chemokine axis.
ISSN:0449-3060
1349-9157
DOI:10.1093/jrr/rru017