Abstract
The inflammation is the pivotal immune responses against bacterial infection. The exaggerated inflammation induced by bacterial infection leads to a severe brain dysfunction, named as septic encephalopathy. Nuclear factor κB (NF-κB) is a critical regulator of innate immunity and inflammatory responses. To directly address the inflammatory state on the spatial and temporal pattern in vivo, we induced septic encephalopathy with group A streptococcus subcutaneously on a previously generated NF-κB-dependent luciferase reporter mouse model. The host-inflammatory reporter signals was examined by the in vivo imaging system (IVIS). Compared to noninfected control mice, the photon intensity of NF-κB activation was emitted in the infected site and reached the peak levels in the brain around 48 h postinfection. To better understand the dysfunction of brain in septic encephalopathy, such as cognitive ability, memory and fever. The brain was separated into three regions, cortex, hippocampus and thalamus, and imaged ex vivo. We found the NF-κB activation signal was emitted in all region. NF-κB-regulated genes, such as TNF-α ,IL-1β, KC and iNOS, were significant elevated in these three brain regions. Using real-time PCR analysis and immunofluorescence staining, the number of activated microglia was also increased in this three brain regions. The activation of astrocyte was found in thalamus especially. Apoptosis monitored by activated-caspoase-3 was found in these three brain regions. After treatment with dominant negative tumor necrosis factor (DN-TNF) together with streptococcal infection, the IL-1β expression was significantly blockage and activated-caspoase-3 positive cells were decreased in three brain region. Taken together, our findings demonstrated that subcutaneous streptococcal infection induced septic encephalopathy through brain NF-κB activation, IL-1β expression, and following increased apoptotic cell in brain. Meanwhile, these central inflammatory responses and streptococcal-induced death can be blocked by peripheral injected DN-TNF, implicating that bacterial infection may activate central NF-κB via circulating TNF-α and provide an alternative therapeutic strategy for human septic encephalopathy.相關論文
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| Date of Award | 2011 |
|---|---|
| Original language | English |
| Supervisor | Pei-Jane Tsai (Supervisor) & Chun-Keung Yu (Supervisor) |