Ethanol & Infection on Mitochondrial Death Signaling

乙醇

• 批准号: 6969616
• 负责人: STEPHEN P KANTROW
• 金额: $ 15.87万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-05 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969616
• 关键词: BCL2 gene /protein; CD95 molecule; apoptosis; bacteria infection mechanism; bacterial pneumonia; biological signal transduction; chronic disease /disorder; cysteine endopeptidases; cytochrome c; ethanol; gene deletion mutation; genetically modified animals; glutathione; host organism interaction; immunosuppressive; laboratory mouse; lymphocyte; mitochondria; oxidative stress; pathologic process; spleen; thymus

Immune activation during severe infection is accompanied by widespread lymphocyte apoptosis. In animal models of lethal infection, lymphocyte apoptosis appears to compromise the host, as strategies to oppose apoptosis improve survival. Alcoholism is associated with an increased risk of severe infection, and depletion of lymphocytes in spleen and thymus dudng chronic ethanol consumption is well recognized. Because ethanol and infection can increase oxidative stress to mitochondria, and mitochondria are central regulators of apoptosis, we hypothesize that ethanol consumption increases mitochondrial injury and death signaling in lymphocytes during infection. We propose to study the effects of chronic ethanol exposure on lymphoid tissue injury during infection with Streptococcus pneumoniae, a common cause of bacteremia in alcoholism and HIV infection. In Specific Aim 1, we will determine the effects of ethanol feeding on apoptosis in 1) spleen and thymus during pneumococcal infection in vivo and 2) splenocytes exposed to a relevant death signal, Fas ligand, in vitro. In Specific Aim 2, we will measure the effects of ethanol feeding and pneumococcal infection on mitochondrial glutathione content and oxidative injury to mitochondrial DNA in lymphoid tissue. In Specific Aim 3, we will evaluate two mitochondria-based strategies for opposing lymphocyte apoptosis in this model by 1) utilizing bcl-2 over-expressing transgenic mice and 2) supplementing mitochondrial glutathione. The results of these experiments will increase our understanding of how chronic ethanol exposure compromises lymphoid tissues directly and during the acute stress of infection.

严重感染期间的免疫激活伴随着广泛的淋巴细胞凋亡。在致死感染的动物模型中，淋巴细胞凋亡似乎会损害宿主，如 对抗细胞凋亡的策略可以提高生存率。酗酒与严重感染的风险增加以及长期乙醇导致脾脏和胸腺中淋巴细胞的消耗有关 消费得到广泛认可。因为乙醇和感染会增加氧化应激 线粒体和线粒体是细胞凋亡的中心调节者，我们假设乙醇 消耗会增加淋巴细胞中的线粒体损伤和死亡信号传导 感染。我们建议研究慢性乙醇暴露对淋巴组织损伤的影响 肺炎链球菌感染期间，肺炎链球菌是酗酒和艾滋病毒感染中菌血症的常见原因。在具体目标 1 中，我们将确定乙醇喂养对 1) 体内肺炎球菌感染期间的脾脏和胸腺以及 2) 体外暴露于相关死亡信号（Fas 配体）的脾细胞细胞凋亡的影响。在具体目标 2 中，我们将测量乙醇喂养和肺炎球菌感染对淋巴组织中线粒体谷胱甘肽含量和线粒体 DNA 氧化损伤的影响。在具体目标 3 中，我们将通过 1) 利用 bcl-2 过表达转基因小鼠和 2) 补充线粒体谷胱甘肽来评估两种基于线粒体的对抗淋巴细胞凋亡的策略。这些实验的结果将加深我们对慢性乙醇暴露如何直接损害淋巴组织以及在急性感染应激期间如何损害淋巴组织的理解。