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

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， 尤其是并发急性肾损伤(AKI)时。脓毒症时AKI的病理生理学继续 人们对此认识不足，导致临床治疗试验持续失败。最近，我们 确定了一种新的脓毒症肾损伤途径，涉及滤过性肾损害的直接相互作用 内毒素和S1近端小管。这种内毒素与S1的相互作用导致严重的过氧化物体损伤 以及下游S2和S3节段的氧化应激。值得注意的是，这条损伤途径没有 对有能力的免疫细胞的要求。在这项建议中，我们继续我们对脓毒症和 AKI通过检测肾脏内毒素预适应的机制。保护性的现象 预适应的独特之处在于，它代表了一种抵抗 内毒素，然而，保存的能力，有效地控制和消除感染。解开 参与内毒素耐受的通路具有识别潜在靶点的巨大潜力 用于预防和治疗人类败血症。从历史上看，预适应一直是 研究免疫细胞及其对反复内毒素暴露的孤立反应。小才是 已知导致整个器官(如肾脏)组织保护的机制。基于 强大的初步数据，这一提议的中心假设是巨噬细胞是必不可少的 预适应保护通路的组成部分。这是一个新的假设，因为它描绘了 巨噬细胞在耐受表型中是一个活跃和有益的参与者。在具体目标1中，我们 将确定巨噬细胞的基本作用，并检查它们与肾小管的相互作用，如 S1网段。在特定目标2中，我们将确定所带来的代谢和转录变化 通过保护S1小管上的巨噬细胞。我们还将确定可直接使用的关键代谢物 来治疗败血症。在特定目标3中，我们将检查保护性巨噬细胞治疗的潜力。 脓毒症采用细胞移植的方法。我们相信，拟议的研究，通过增加我们对 内毒素预适应，具有巨大的翻译潜力，将揭示一种新的和全球的 脓毒症及脓毒症所致急性肾功能衰竭的防治探讨

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.