Journal
JOURNAL OF RADIATION RESEARCH
Volume 55, Issue 4, Pages 803-811Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jrr/rru017
Keywords
brain radiation necrosis; CXCL12/CXCR4 chemokine axis; inflammation; microglia; pro-inflammatory cytokine
Funding
- Japanese Ministry of Education, Culture, Sports, Science, and Technology [23390355, 24659658, 23592145]
- Grants-in-Aid for Scientific Research [23592145, 23390355, 26293327, 26462222, 24659658, 26462192] Funding Source: KAKEN
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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-1 alpha, CXCL12, CXCR4, GFAP, CD68, hGLUT5, CD45, IL-1 alpha, IL-6 TNF-alpha 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-1 alpha 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-1 alpha, IL-6 and TNF-alpha 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-1 alpha, which is well known as a transactivator of VEGF and of the CXCL12/CXCR4 chemokine axis.
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