Very little is known about radiation-induced gene expression in vivo and its radiobiological significance. We have shown that irradiation induces TNF-alpha and IL-1 production in the mouse brain. mRNA levels peak at 6 hours and fall by 24 hours. ICAM-1, anti-chymotrypsin, and glial fibrillary acid protein also increased with a slightly delayed time scale. This represents a dose-dependent, co-ordinated and transient, acute phase molecular response to irradiation. The radiation-induced acute phase response can be inhibited by high dose steroids. inhibition of the acute phase response will be used to determine if it influences subacute and late molecular, cellular, and functional events. The pathogenesis of brain injury in this model is associated with reversible neurological changes at 2-3 months followed by loss of oligodendrocytes and demyelination leading to death at 6-8 months. Our molecular data indicate that at 2 months after 25 Gy (LD10/180), TNF- alpha, ICAM-1, and GFAP levels are re-elevated, but at 6 months, only TNF-alpha is markedly increased. This helped to identify TNF-alpha as a specific focus of the proposal, along with the considerable body of data in support of the hypothesis that TNF-alpha is a prime initiator of pathogenic responses and can mediate damage in demyelinating diseases. Blocking antibodies to TNF-alpha and mice with target mutations in TNF-R1 and/or TNF-R2 will be used to identify the role of TNF-alpha in radiation-induced brain injury and the pathways involved. Strategies for therapeutic intervention to increase the effectiveness of radiotherapy for brain cancer might be generated as a result of this study.
| McBride, William H; Chiang, Chi-Shiun; Olson, Jennifer L et al. (2004) A sense of danger from radiation. Radiat Res 162:1-19 |
| Daigle, J L; Hong, J H; Chiang, C S et al. (2001) The role of tumor necrosis factor signaling pathways in the response of murine brain to irradiation. Cancer Res 61:8859-65 |
| Hong, J H; Chiang, C S; Sun, J R et al. (1997) Induction of c-fos and junB mRNA following in vivo brain irradiation. Brain Res Mol Brain Res 48:223-8 |
