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: 9765302
• 负责人: Pierre C Dagher
• 金额: $ 37.51万
• 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/9765302
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; 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 Response; 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; Phagocytes; 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; Subgroup; Testing; Therapeutic; Therapeutic Clinical Trial; Therapeutic Intervention; Tissues; United States National Institutes of Health; Work; base; expectation; fascinate; fighting; gram-negative sepsis; human disease; improved; in vivo; interest; macrophage; metabolic profile; metabolomics; mortality; novel; outcome forecast; preconditioning; preservation; 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.

革兰氏阴性败血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（AKI）时。脓毒症 AKI 的病理生理学仍在继续 对其了解甚少，导致临床治疗试验持续失败。最近，我们 确定了脓毒症肾损伤的新途径，涉及过滤之间的直接相互作用 内毒素和S1近曲小管。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 片段的氧化应激。值得注意的是，这种损伤途径没有 对有能力的免疫细胞的要求。在本提案中，我们继续对败血症和 通过检查肾内毒素预处理的 AKI 机制。保护现象 预处理的独特之处在于它代表了对有害影响的抵抗状态 内毒素，并且保留了有效遏制和消除感染的能力。揭开谜底 涉及内毒素耐受的途径对于识别潜在靶标具有巨大潜力 用于预防和治疗人类败血症。从历史上看，预处理一直是 研究了免疫细胞及其对重复内毒素暴露的单独反应。小的是 了解导致肾脏等整个器官的组织保护的机制。基于 强有力的初步数据，该提案的中心假设是巨噬细胞至关重要 预处理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且有益的参与者。在具体目标 1 中，我们 将确定巨噬细胞的重要作用并检查它们与肾小管的串扰，例如 S1 段。在具体目标 2 中，我们将确定所带来的代谢和转录组变化 S1 肾小管上的保护性巨噬细胞。我们还将确定可直接使用的关键代谢物 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的潜力 细胞转移方法中的败血症。我们相信，拟议的研究可以通过增加我们的理解 内毒素预处理的研究具有巨大的转化潜力，将揭示一种新颖的、全球性的 预防和治疗脓毒症和脓毒症引起的 AKI 的方法。