title: Inflammation as well as angiogenesis may participate in the pathophysiology of brain radiation necrosis.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Yoritsune
authors.affiliation: Department of Neurosurgery, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
authors.forename: Motomasa
authors.initials: M
authors.lastname: Furuse
authors.affiliation: Department of Pathology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kuwabara
authors.affiliation: Department of Neurosurgery, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
authors.forename: Tomo
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Department of Neurosurgery, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
authors.forename: Naosuke
authors.initials: N
authors.lastname: Nonoguchi
authors.affiliation: Department of Neurosurgery, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kawabata
authors.affiliation: Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
authors.forename: Hana
authors.initials: H
authors.lastname: Hayasaki
authors.affiliation: Department of Neurosurgery, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kuroiwa
authors.affiliation: Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ono
authors.affiliation: Department of Pathology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
authors.forename: Yuro
authors.initials: Y
authors.lastname: Shibayama
authors.affiliation: Department of Neurosurgery, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan neu070@poh.osaka-med.ac.jp.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Miyatake
mesh_terms: D000328:Adult; D000368:Aged; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D001932:Brain Neoplasms / Q000532:radiotherapy; D018925:Chemokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000209:etiology; D011832:Radiation Injuries / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D011878:Radiotherapy / Q000009:adverse effects*; D019707:Receptors, Chemokine / Q000378:metabolism
chemical_list: D018925:Chemokines; D019707:Receptors, Chemokine
keywords: CXCL12/CXCR4 chemokine axis; brain radiation necrosis; inflammation; microglia; pro-inflammatory cytokine