Protective pathways in sepsis-induced renal injury

脓毒症引起的肾损伤的保护途径

• 批准号: 9318114
• 负责人: Pierre C Dagher
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318114
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Antioxidants; Biochemical; CD14 gene; Cells; Data; Disease; Dose; End stage renal failure; Endotoxins; Exposure to; Failure; Functional disorder; Goals; Health; Human; Image; Imaging Techniques; Immune; Immunosuppression; Infection; Inflammatory Response; Injury; Intensive Care Units; Investigation; Kidney; Kidney Failure; Knowledge; Mediating; Microscopy; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Organ; Outcome; Oxidative Stress; Participant; Pathway interactions; Patient-Focused Outcomes; Patients; Phagocytes; Phenotype; Population; Prevention; Prevention approach; Public Health; Publishing; Quality of life; Renal Tissue; Renal tubule structure; Research; Resistance; Role; Route; Secondary to; Sepsis; Signal Transduction; Source; Subgroup; TLR4 gene; Techniques; Testing; Therapeutic; Therapeutic Clinical Trial; Therapeutic Intervention; Tissues; Veterans; Work; base; expectation; fascinate; fighting; heme oxygenase-1; human disease; improved; in vivo; interest; intravital imaging; macrophage; metabolomics; mortality; novel; outcome forecast; preconditioning; prevent; public health relevance; response; septic; signature molecule; spatiotemporal; targeted treatment; tool

 DESCRIPTION (provided by applicant): 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 trial. 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 in 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 in inducing renal endotoxin tolerance by examining chimeric mice lacking myeloid TLR4 and CD14. We will fully characterize these macrophages by flow techniques and image their spatial and temporal interactions with renal tubules using intra vital microscopy. In specific aim 2, we will examine th potential of protective macrophages to prevent and treat sepsis using cell transfer approaches. In specific aim 3, we will examine in detail the roles of macrophage CD14, heme oxygenase 1 (HO1) as essential molecules of the macrophage phenotype necessary for inducing renal protection. We will also examine the potential roles of various metabolites involved in macrophage differentiation and function as therapeutic tools against sepsis. These three aims will identify the macrophage as the most central player in renal protective preconditioning. These aims will also identify pathways controlled by CD14 and TRIF that are potential targets for therapeutic intervention in septic patients. 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.

 描述（由申请人提供）： 革兰氏阴性脓毒症仍然是住院患者死亡率和发病率的主要原因，特别是当并发急性肾损伤（阿基）时。脓毒症中阿基的病理生理学仍然知之甚少，导致临床治疗试验持续失败。最近，我们发现了一种新的途径，在脓毒症肾损伤涉及直接相互作用之间的过滤内毒素和S1近端小管。这种内毒素-S1相互作用导致下游S2和S3段严重的过氧化物酶体损伤和氧化应激。值得注意的是，这种损伤途径不需要有能力的免疫细胞。在这个建议中，我们继续我们的研究脓毒症和阿基通过检查肾内毒素预处理的机制。保护性预处理的现象是独特的，因为它代表了一种抵抗内毒素有害作用的状态，但保留了有效控制和消除感染的能力。揭示内毒素耐受的相关通路对于确定预防和治疗人类脓毒症的潜在靶点具有巨大的潜力。从历史上看，已经在免疫细胞及其对重复内毒素暴露的孤立反应中研究了预处理。对整个器官（如肾脏）的组织保护机制知之甚少。基于强有力的初步数据，该提议的中心假设是巨噬细胞是预处理保护途径的重要组成部分。这是一个新的假设，因为它描述了巨噬细胞作为一个积极的和有益的参与者在耐受表型。在具体目标1中，我们将通过检查缺乏髓样TLR 4和CD 14的嵌合小鼠来确定巨噬细胞在诱导肾内毒素耐受中的重要作用。我们将充分表征这些巨噬细胞的流动技术和图像的空间和时间的相互作用与肾小管使用活体显微镜。在具体目标2中，我们将使用细胞转移方法来检查保护性巨噬细胞预防和治疗脓毒症的潜力。在具体目标3中，我们将详细研究巨噬细胞CD 14，血红素加氧酶1（HO 1）作为诱导肾保护所必需的巨噬细胞表型的基本分子的作用。我们还将研究参与巨噬细胞分化的各种代谢物的潜在作用，并作为对抗脓毒症的治疗工具。这三个目标将确定巨噬细胞作为最核心的球员在肾脏保护性预处理。这些目标还将确定由CD 14和TRIF控制的途径，这些途径是脓毒症患者治疗干预的潜在靶点。我们相信，通过增加我们对内毒素预处理的理解，拟议的研究具有巨大的转化潜力，并将揭示预防和治疗脓毒症和脓毒症诱导的阿基的新的全球方法。