LPS Efflux from Host Cells to Plasma Lipoproteins

LPS 从宿主细胞流出至血浆脂蛋白

• 批准号: 7337301
• 负责人: RICHARD L. KITCHENS
• 金额: $ 29.02万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337301
• 关键词: ATP-Binding Cassette Transporters; Animals; Apolipoprotein E; Apolipoproteins; Apolipoproteins C; Atherosclerosis; Bacterial Infections; Cells; Complex; Endotoxins; Functional disorder; Genes; Immune response; Inflammation; Inflammatory; LDL-Receptor Related Protein 1; Lead; Lipids; Lipopolysaccharides; Lipoprotein Binding; Lipoproteins; Molecular; Mus; Plasma; Regulation; Resistance; Role; Sepsis; Thinking; Tissues; Toxic effect; bacterial resistance; in vivo; macrophage; monocyte; novel; prevent

DESCRIPTION (provided by applicant): The stimulatory effects of bacterial lipopolysaccharide (LPS or endotoxin) can enhance beneficial innate immune responses in animal hosts, whereas its potential toxicity is thought to contribute importantly to the pathophysiology of sepsis. Plasma lipoproteins bind and neutralize LPS and help to control monocyte activation by promoting LPS efflux from these cells. In contrast to circulating monocytes, we found that differentiated macrophages can promote rapid LPS efflux without a requirement for any plasma constituent. ATP-binding cassette transporter A1 (ABCA1) and endogenously synthesized apolipoprotein E (apoE) can remove macrophage-associated LPS by mechanisms that are similar to those that remove inflammatory host lipids from macrophages and help reduce atherosclerosis. Since apoE is known to increase resistance to LPS toxicity and bacterial infection, we hypothesize that macrophage-derived apolipoproteins and ABC transporters help control local inflammation by decreasing LPS bioactivity and preventing LPS accumulation in tissues. Our Specific Aims are to determine: (I) The molecular mechanisms of LPS efflux from macrophages, specifically the roles of ABCA1 and macrophage-derived apolipoproteins (apoE and apoC-l). (II) The disposition and bioactivity of the LPS that is released from macrophages, primarily in terms of its association with apoE and apoC-l. We will also study LPS-apoE interactions with apoE receptors. (Ill) The regulation of apolipoproteins and related genes during inflammation and sepsis in mice, and the effects of macrophage specific expression or deficiency of apoE in vivo to determine the impact of macrophage-derived apoE on local inflammation, innate immune responses, and resistance to bacterial infection. It is hoped that these studies will define novel mechanisms for the control of local inflammation by macrophages and apolipoproteins and that these studies will lead to improvements in the management of sepsis.

描述（由申请人提供）：细菌脂多糖（LPS或内毒素）的刺激作用可以增强动物宿主中有益的先天免疫反应，而其潜在毒性被认为对脓毒症的病理生理有重要作用。血浆脂蛋白结合和中和LPS，并通过促进这些细胞的LPS外排来帮助控制单核细胞激活。与循环单核细胞相比，我们发现分化的巨噬细胞可以促进快速LPS外排，而无需任何等离子体成分。 ATP结合盒转运蛋白A1（ABCA1）和内源合成的载脂蛋白E（APOE）可以通过与去除巨噬细胞中去除炎性宿主脂质的机制去除与巨噬细胞相关的LP，并帮助减少动脉粥样硬化。由于已知APOE会增加对LPS毒性和细菌感染的耐药性，因此我们假设巨噬细胞衍生的载脂蛋白和ABC转运蛋白有助于通过降低LPS生物活性并防止LPS在组织中积累。我们的具体目的是确定：（i）巨噬细胞中LPS外排的分子机制，特别是ABCA1和巨噬细胞衍生的载脂蛋白（APOE和APOC-L）的作用。 （ii）从巨噬细胞释放的LP的性格和生物活性，主要是与APOE和APOC-L的关联。我们还将研究LPS-APOE与APOE受体的相互作用。 （病）调节小鼠炎症和败血症期间载脂蛋白和相关基因的调节，以及巨噬细胞特异性表达或体内ApoE的影响，以确定巨噬细胞衍生的APOE对局部炎症，先天免疫反应以及对细菌感染的抗性的影响。希望这些研究能够定义巨噬细胞和载脂蛋白控制局部炎症的新机制，这些研究将导致败血症治疗的改善。