Radiation therapy has been most commonly used modality in the treatment of brain tumors. About 200,000 patients with brain tumors are treated with either partial large field or whole brain irradiation every year in the United States. The use of radiation therapy for treatment of brain tumor, however, can subsequently lead to devastating functional deficits several months to years after treatment. Unfortunately, there are no known successful treatments and effective strategies for mitigating radiation-induced brain injury. In addition, the specific mechanisms by which irradiation causes brain injury in normal tissues are not fully understood. A deeper understanding of the molecular mechanisms underlying these phenomena could enable the development of more effective therapies to contribute to long-term disease suppression or even cure. Therefore,the primary goal of this research project was to determine the molecular mechanisms responsible for radiation-induced brain injury in normal tissues. In the first study, the effects of whole brain irradiation on pro-inflammatory pathways in the brain were examined. Results demonstrated that brain irradiation induces regionally specific alterations in pro-inflammatory environments through activation of pro-inflammatory transcription factors (e.g., activator protein-1 (AP-1),nuclear factor-κB (NF-κB), and cAMP response element-binding protein (CREB)) and overexpression of pro-inflammatory mediators (e.g., tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1)) in brain. This study provides evidence for a differential induction of pro-inflammatory mediators in specific brain regions that have importance for the neurological/neuropathological consequences of irradiation. In the second study, a mathematical model describing radiation-induced mRNA and protein expression kinetics of TNF-α in hippocampus was reconstructed. This study demonstrated that the reaction kinetic model could predict protein expression levels of TNF-α in cortex, suggesting that this model could be used to predict protein expression levels of pro-inflammatory mediators in other parts of the brain. In the third study, the effects of aging on radiation-mediated impairment of immune responses in brain were examined. Results showed that radiation-induced acute inflammatory responses, such as overexpression of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6),adhesion molecules (e.g., intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin), chemokine MCP-1, and matrix metalloproteinase-9 (MMP-9), are significantly impaired in aged brain. This study suggests that reduced production of pro-inflammatory mediators in response to irradiation compromises the normal host defense mechanisms in damaged brain tissue and subsequently leads to impaired repair/remodeling responses in old individuals. In the fourth study, the effects of irradiation on MMPs/tissue inhibitor of metalloproteinases (TIMPs) and extracellular matrix (ECM) degradation in brain were examined. Results demonstrated that whole brain irradiation induces an imbalance between MMPs and TIMPs expression, increases gelatinase activity, and degrades collagen type IV in the brain. This study suggests that a radiation-induced imbalance between MMP-2 and TIMP-2 expression may have an important role in the pathogenesis of brain injury by degrading ECM components of the blood-brain barrier (BBB) basement membrane. In the fifth study, the effects of irradiation on angiogenic factors and vessel rarefaction in brain were examined. Results demonstrated that whole brain irradiation decreases endothelial cell (EC) proliferation, increases EC apoptosis, and differentially regulates the expression of angiogenic factors such as angiopoietin-1 (Ang-1), Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) in brain. This study suggests that radiation-induced differential regulation of angiogenic factors may be responsible for vessel rarefaction. In summary, the results from these studies demonstrated that whole brain irradiation induces brain injury by triggering pro-inflammatory pathways, degrading extracellular matrix, and altering physiologic angiogenesis. Therefore, this work may be beneficial in defining a new cellular and molecular basis responsible for radiation-induced brain injury. Furthermore, it may provide new opportunities for prevention and treatment of brain tumor patients who are undergoing radiotherapy. / Ph. D.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25195号 / 医博第5081号 / 新制||医||1072(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 鈴木 実, 教授 椛島 健治, 教授 中本 裕士 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM