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

基本信息

批准号：
10653145
负责人：
Pierre C Dagher
金额：
$ 53.45万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-25 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653145
关键词：
Acute Renal Failure with Renal Papillary Necrosis Affect Animals Biochemical Bioenergetics Biological Markers Bone Marrow Catalysis Cell Communication Cell physiology Cells Clinical Clinical Trials Complex Data Degradation Pathway Deuterium Oxide Development Disadvantaged Endotoxins Enzymes Free Radicals Functional disorder Generations Goals Health Homeostasis Hospitalization Injury Injury to Kidney Kidney Knock-in Mouse Label Laboratories Macrophage Maintenance Measures Metabolic Pathway Modeling Modification Molecular Molecular Target Morbidity - disease rate Mouse Strains Mus Nucleic Acids Organ Oxidases Oxidative Stress Oxidoreductase Pathologic Pathway interactions Patients Precision therapeutics Prevention Purines Reaction Reactive Oxygen Species Role Sepsis Signal Transduction System Techniques Testing Therapeutic Tissues Tubular formation Uric Acid Work XDH gene arms race bactericide cell type effective therapy kidney cell metabolomics mortality oxidation oxidative damage pathogen pharmacologic preconditioning protective pathway purine metabolism renal damage sensor septic targeted treatment therapeutic target transcriptomics uptake urinary

项目摘要

Sepsis-induced acute kidney injury remains a major clinical problem with no effective therapy established to date. Although potential therapeutic targets have been identified and tested in clinical trials, none of them has proven to be effective, underscoring the complexity of sepsis pathophysiology. Work from our laboratory identified disturbances in cell-cell communication as a major feature underlying the complex pathophysiology of sepsis-induced kidney damage. For example, pathologic signaling from S1 tubules to downstream S2/S3 tubules was a major pathway of renal injury in sepsis. Indeed, we identified the S1 proximal tubular segment as a major sensor and sink for filtered endotoxin. This S1 uptake of endotoxin resulted in severe oxidative stress and damage to downstream S2/S3 segments. Targeted S1 transcriptomics and tissue metabolomics revealed that purine metabolism is markedly altered in septic S1 proximal tubules. This shift is catalyzed by xanthine oxidoreductase, a key enzyme in the purine degradation pathway. This enzyme functions as a dehydrogenase (XDH) in its native form but is readily converted to an oxidase (XO) through sulfhydryl oxidation or proteolytic modification. Whereas catalysis by XDH does not generate free radicals, XO is a strong pro-oxidant that generates deleterious reactive species. Furthermore, the pro-oxidant XO is secreted into the urinary lumen and can therefore cause damage to downstream segments. In contrast, XO expression in macrophages may be beneficial because it stimulates the bactericidal potential of these cells through generation of reactive species. It is one goal of this proposal to establish the relative roles of XO versus XDH in S1 and macrophages in septic kidneys. Moreover, because XO/XDH is involved in the final degradation of purines, the changes in XO/XDH activity will not only affect the generation of reactive species but will also have an upstream impact on the size of purine pools. It is the second goal of this proposal to determine the overall flux of purine metabolites and their contributions to purine homeostasis in sepsis.

脓毒症引起的急性肾损伤仍然是一个主要的临床问题，目前尚无有效的治疗方法日期。尽管已经确定了潜在的治疗靶点并在临床试验中进行了测试，但没有一个靶点被证实有效。被证明是有效的，强调了脓毒症病理生理学的复杂性。在我们的实验室工作确定细胞间通讯紊乱是复杂病理生理学的一个主要特征脓毒症引起的肾脏损害。例如，从 S1 小管到下游 S2/S3 的病理信号传导肾小管是脓毒症肾损伤的主要途径。事实上，我们将 S1 近端管状段确定为过滤内毒素的主要传感器和接收器。 S1 摄取内毒素导致严重的氧化应激以及下游 S2/S3 段的损坏。揭示靶向 S1 转录组学和组织代谢组学脓毒症 S1 近端小管中的嘌呤代谢显着改变。这种转变是由黄嘌呤催化的氧化还原酶，嘌呤降解途径中的关键酶。这种酶起到脱氢酶的作用 (XDH) 以其天然形式存在，但很容易通过巯基氧化或蛋白水解转化为氧化酶 (XO) 修改。 XDH 的催化作用不会产生自由基，而 XO 是一种强氧化剂，产生有害的活性物质。此外，促氧化剂 XO 被分泌到尿腔中，因此可能会对下游部分造成损害。相反，巨噬细胞中的 XO 表达可能是有益的，因为它通过产生活性物质来刺激这些细胞的杀菌潜力。该提案的一个目标是确定 XO 与 XDH 在 S1 中和脓毒症巨噬细胞中的相对作用肾脏。而且，由于XO/XDH参与嘌呤的最终降解，因此XO/XDH的变化活性不仅会影响活性物质的产生，还会对上游的尺寸产生影响嘌呤池。该提案的第二个目标是确定嘌呤代谢物的总体通量和他们对脓毒症嘌呤稳态的贡献。