Endotoxin preconditioning as a model to uncover protective pathways in sepsis-induced renal injury.

内毒素预处理作为模型揭示脓毒症引起的肾损伤的保护途径。

• 批准号: 9172789
• 负责人: Pierre C Dagher
• 金额: $ 37.15万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-25 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172789
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Cells; Chemotactic Factors; Data; Disease; Dose; End stage renal failure; Endotoxins; Exposure to; Failure; Functional disorder; Goals; Health; Human; Immune; Immunosuppression; Infection; Inflammatory; Injury; Intensive Care Units; Investigation; Kidney; Knowledge; Mediating; Metabolic; Metabolism; Mission; Modeling; Molecular; Morbidity - disease rate; Organ; Outcome; Oxidative Stress; Participant; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Prevention; Prevention approach; Property; Public Health; Publishing; Quality of life; Renal Tissue; Renal tubule structure; Research; Resistance; Role; Sepsis; Signal Transduction; Small Interfering RNA; Staging; Subgroup; Testing; Therapeutic; Therapeutic Clinical Trial; Therapeutic Intervention; Tissues; United States National Institutes of Health; Work; base; expectation; fascinate; fighting; human disease; improved; in vivo; interest; macrophage; metabolic profile; metabolomics; mortality; novel; outcome forecast; preconditioning; prevent; response; targeted treatment; transcriptomics

Gram-negative sepsis remains a major cause of mortality and morbidity in hospitalized patients, especially when complicated by acute kidney injury (AKI). The pathophysiology of AKI in sepsis continues to be poorly understood resulting in the persistent failure of clinical therapeutic trials. Recently, we identified a novel pathway of renal injury in sepsis involving direct interactions between filtered endotoxin and S1 proximal tubules. This endotoxin-S1 interaction resulted in severe peroxisomal damage and oxidative stress in downstream S2 and S3 segments. Remarkably, this pathway of injury had no requirement for competent immune cells. In this proposal, we continue our investigation of sepsis and AKI by examining the mechanisms of renal endotoxin preconditioning. The phenomenon of protective preconditioning is unique in that it represents a state of resistance to the deleterious effects of endotoxin and yet, a preserved ability to effectively contain and eliminate infections. Unraveling the pathways involved in endotoxin tolerance has great potential for identifying potential targets that can be used for the prevention and treatment of human sepsis. Historically, preconditioning has been investigated in immune cells and their isolated responses to repeated endotoxin exposure. Little is known about the mechanisms leading to tissue protection in whole organs such as the kidney. Based on strong preliminary data, the central hypothesis of this proposal is that macrophages are essential components of the protective pathways of preconditioning. This is a novel hypothesis because it depicts the macrophage as an active and beneficial participant in the tolerant phenotype. In specific aim 1, we will establish the essential role of macrophages and examine their cross-talk with renal tubules such as the S1 segment. In specific aim 2, we will determine the metabolic and transcriptomic changes imparted by protective macrophages on S1 tubules. We will also identify key metabolites that can be used directlt to treat sepsis. In specific aim 3, we will examine the potential of protective macrophages to treat sepsis in a cell transfer approach. We believe that the proposed studies, by increasing our understanding of endotoxin preconditioning, have great translational potential and will uncover a novel and global approach to the prevention and treatment of sepsis and sepsis-induced AKI.

革兰氏阴性脓毒症仍然是住院患者死亡和发病的主要原因， 尤其是当并发急性肾损伤（阿基）时。脓毒症中阿基的病理生理学继续 对这些问题的认识不足，导致临床治疗试验的持续失败。最近我们 发现了一种新的脓毒症肾损伤途径， 内毒素和S1近端小管。这种内毒素-S1相互作用导致严重的过氧化物酶体损伤 以及下游S2和S3节段中的氧化应激。值得注意的是，这种损伤途径没有 需要有能力的免疫细胞在这个建议中，我们继续我们的调查败血症， 内毒素预处理对急性肾损伤的保护作用。保护现象 预处理是独特的，因为它代表了一种抵抗有害影响的状态， 内毒素，但保留了有效控制和消除感染的能力。Unraveling the 参与内毒素耐受性的途径具有很大的潜力，用于鉴定可以 用于预防和治疗人败血症。从历史上看，预处理一直是 研究免疫细胞及其对重复内毒素暴露的孤立反应。之甚少 目前还不清楚导致整个器官（如肾脏）组织保护的机制。基于 强有力的初步数据，这一建议的中心假设是，巨噬细胞是必不可少的 预处理的保护途径的组成部分。这是一个新颖的假设，因为它描述了 巨噬细胞作为耐受表型的积极和有益的参与者。在具体目标1中，我们 将建立巨噬细胞的基本作用，并检查它们与肾小管的相互作用， S1段。在具体的目标2中，我们将确定代谢和转录组学的变化， 由S1小管上的保护性巨噬细胞产生我们还将确定可直接用于治疗的关键代谢物。 来治疗败血症在具体目标3中，我们将研究保护性巨噬细胞治疗 脓毒症的细胞转移方法。我们认为，通过增加我们的了解， 内毒素预处理，具有很大的翻译潜力，将揭示一个新的和全球性的 预防和治疗脓毒症和脓毒症诱导的阿基的方法。