Acute Ethanol-Induced Innate Immune Response in Liver

急性乙醇诱导的肝脏先天免疫反应

• 批准号: 7211497
• 负责人: RICHARD A RIPPE
• 金额: $ 24.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211497
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Adaptor Signaling Protein; Address; Adenovirus Vector; Adenoviruses; Alcoholic Liver Diseases; Alcohols; Animals; CD14 Antigen; CD14 gene; Cell Line; Cells; Chronic; Complex; Condition; Cuprozinc Superoxide Dismutase; Cytokine Activation; Data; Dominant-Negative Mutation; Electrophoretic Mobility Shift Assay; Endotoxins; Estrogen Receptors; Estrogens; Ethanol; Ethanol toxicity; Exposure to; Female; Gender; Gene Delivery; Gene Expression; Generations; Hour; Human; Immune response; Immunoprecipitation; Indium; Inflammatory; Injury; Knock-out; Knockout Mice; Kupffer Cells; Laboratories; Liver; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; NADPH Oxidase; NF-kappa B; Natural Immunity; Numbers; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Pattern; Personal Satisfaction; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphotransferases; Pilot Projects; Play; Predisposition; Production; Protein Overexpression; Purpose; RNase protection assay; Recombinants; Regulation; Reporting; Resistance; Role; Serum; Sex Characteristics; Signal Transduction; Superoxide Dismutase; Superoxides; TNFRSF5 gene; Techniques; Technology; Testing; Time; Toll-Like Receptor 2; Transaminases; Transcription Factor AP-1; Transcriptional Activation; Transgenes; Transgenic Animals; Tumor Necrosis Factor-alpha; Up-Regulation; Week; Western Blotting; Wit; activating transcription factor; alcohol response; base; cytokine; endotoxin receptor; feeding; gene therapy; human TNF protein; in vivo; inhibitor/antagonist; kinase inhibitor; macrophage; male; mutant; novel strategies; pathogen; receptor; receptor expression; research study; response; scavenger receptor; src-Family Kinases; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The involvement of endotoxin in early alcohol-induced liver injury is well established; supporting the hypothesis, that pathogenesis involves aspects of innate immunity and inflammatory mediators. A number of reports have clearly demonstrated that Kupffer cells play a critical role in the pathogenesis due to ethanol. Specifically, it was shown that mice deficient in the endotoxin receptor CD14, which is primarily expressed on Kupffer cells, were resistant to chronic alcohol-induced liver injury. These data suggest that CD14 signaling may be a critical component in alcohol-related liver injury. The overall hypothesis is that LPS from the gut activates Kupffer cells causing an increase in oxidant production and subsequent TNF-alpha release. This hypothesis is strongly supported by a number of studies using gene therapy, knockout and transgenic animals, as well as an in vivo mouse intragastric ethanol-feeding model. Despite a great amount of new information regarding the role of endotoxin in ethanol-induced liver injury, critical gaps still exist in our understanding. For example, the signaling mechanisms involved in LPS- induced oxidant production, the regulation of CD14 and related signaling components in pathogenesis, and the molecular mechanisms determining gender- related differences in injury remain unknown. The purpose of this application is to address the following underlying hypotheses: 1. PI3 kinase mediates LPS-induced NADPH oxidase generation of superoxide in Kupffer cells. 2. Oxidant-sensitive transcription factors NF-kappaB and AP-1 regulate CD14 expression following acute ethanol administration. 3. Gender differences in regulation of innate immune response and transcription factor activation are key to increased susceptibility to ethanol-induced pathogenesis in females. The aims below will use gene delivery techniques and knockout mouse technology to address these critical questions related to roles of LPS, PI3 kinase activation, and CD14 expression in both acute ethanol and chronic ethanol toxicity.

描述（由申请人提供）：内毒素参与早期酒精引起的肝损伤；支持这一假设，即发病机理涉及先天免疫和炎症介质的各个方面。 许多报告清楚地表明，库普弗细胞在乙醇引起的发病机理中起关键作用。具体而言，显示出主要在库普弗细胞上表达的内毒素受体CD14缺乏的小鼠对慢性酒精诱导的肝损伤具有抗性。 这些数据表明，CD14信号传导可能是酒精相关肝损伤的关键成分。 总体假设是，来自肠道的LP会激活库普弗细胞，从而导致氧化剂产生和随后的TNF-Alpha释放。 通过基因疗法，基因敲除和转基因动物以及体内小鼠胃内乙醇喂养模型的许多研究，这一假设得到了许多研究。 尽管有关内毒素在乙醇引起的肝损伤中的作用的大量新信息，但我们的理解中仍然存在关键差距。例如，与LPS诱导的氧化剂产生有关的信号传导机制，发病机理中CD14和相关信号传导成分的调节以及确定损伤性别相关差异的分子机制仍然未知。 该应用的目的是解决以下基本假设：1。PI3激酶介导LPS诱导的NADPH氧化酶在Kupffer细胞中的产生。 2。氧化剂敏感的转录因子NF-kappab和AP-1调节急性乙醇后的CD14表达。 3。先天免疫反应和转录因子激活调节中性别差异是增加女性对乙醇引起的发病机理的敏感性的关键。 下面的目的将使用基因递送技术和敲除小鼠技术来解决与LP，PI3激酶激活和CD14在急性乙醇和慢性乙醇毒性中的表达有关的关键问题。

项目成果

Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis.

• DOI: 10.1002/hep.23292
• 发表时间: 2010-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Kremer, Michael;Thomas, Emmanuel;Milton, Richard J.;Perry, Ashley W.;van Rooijen, Nico;Wheeler, Michael D.;Zacks, Steven;Fried, Michael;Rippe, Richard A.;Hines, Ian N.
• 通讯作者: Hines, Ian N.

Src kinase participates in LPS-induced activation of NADPH oxidase.

• DOI: 10.1016/j.molimm.2009.10.012
• 发表时间: 2010-01
• 期刊: MOLECULAR IMMUNOLOGY
• 影响因子: 3.6
• 作者: Check, Jennifer;Byrd, Christy L.;Menio, Jade;Rippe, Richard A.;Hines, Ian N.;Wheeler, Michael D.
• 通讯作者: Wheeler, Michael D.

Multipotent stem/progenitor cells in the human foetal biliary tree.

• DOI: 10.1016/j.jhep.2012.07.013
• 发表时间: 2012-11
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: R. Semeraro;G. Carpino;V. Cardinale;P. Onori;R. Gentile;A. Cantafora;A. Franchitto;C. Napoli;M. Anceschi;R. Brunelli;D. Bosco;A. Torrice;L. Reid;E. Gaudio;D. Alvaro