Mechanisms of susceptibility to sepsis after acute kidney injury

急性肾损伤后脓毒症易感性机制

基本信息

批准号：
9130408
负责人：
Sarah g Faubel
金额：
$ 38.88万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2016-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130408
关键词：
Acute Lung Injury Acute Renal Failure with Renal Papillary Necrosis Admission activity Agreement Air Alveolar Alveolar Macrophages Alveolus Animal Model Anti-Inflammatory Agents Anti-inflammatory Area Bacteremia Bacteria Bacterial Counts Bacterial Translocation Blood Blood Circulation Blood Flow Cytometry Breathing Bronchoalveolar Lavage Fluid CXCL1 gene Cessation of life Clinical Trials Communities Complication Confocal Microscopy Creatinine Data Diagnosis Endotoxins Epithelial Epithelial Cells Gram-Negative Bacteria Grant Health Hospital Mortality Hospitals Hour Immune In Vitro Infection Inflammation Inflammatory Response Injury Intensive Care Units Interleukin-6 Label Lung Lung Inflammation Measures Mediating Methods Molecular Mus Neutrophil Infiltration Patients Peptide Hydrolases Permeability Phagocytosis Phase Pneumonia Predisposition Prevention Production Proteins Pseudomonas aeruginosa Publishing Research Sepsis Serum Severities Signal Transduction TNF gene Tight Junctions Translations Tumor Necrosis Factor-alpha alveolar epithelium base bioluminescence imaging claudin 4 cytokine immune function improved in vivo killings luciferin lung injury mortality neutrophil operation prevent research study success therapy development time use

项目摘要

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is common and increases mortality. AKI complicates up to 20% of hospital admissions and 30 to 50% of ICU admissions. Sepsis occurs in 40-45% of patients after AKI diagnosis and doubles mortality. No therapy is available to treat AKI or prevent its complications. To date, translation of bench research into therapies for AKI has been completely unsuccessful, as all of the trials examining therapies that were effective in animal models failed in patients with AKI. Numerous explanations have been offered, with variable degree of agreement on the most critical barriers to success. One notable area of agreement in the AKI community is that therapies in clinical trials were administered too late, or in the inappropriate phase of AKI, to be effective. In this grant, we investigate the mechanisms by which AKI predisposes to sepsis from pneumonia. Since sepsis occurs after the diagnosis of AKI (based on a serum creatinine definition of AKI), we believe that this complication is highly amenable to anticipation and prevention. Thus, if the aims of this proposal are achieved, an immediately applicable target to improve survival in patients with AKI will be identified. Our overall hypothesis is that AKI primes alveolar macrophages to exert an exuberant inflammatory response when exposed to endotoxin or gram negative bacteria. We propose that exuberant inflammatory response mediates lung inflammation, loss of tight junction proteins, and increased epithelial permeability which facilitates translocation of bacteria into the circulation resulting in bacteremia and sepsis. We have three Specific Aims: 1) Determine if acute kidney injury (AKI) causes immune priming of alveolar macrophages; 2) Determine if AKI-primed alveolar macrophages mediate lung epithelial injury; 3) Determine if lung epithelial injury from AKI-primed alveolar macrophages mediates translocation of bacteria into the circulation during pneumonia. Immune priming of alveolar macrophages will be ascertained in vivo, and in vitro as judged by excessive TNF-a production in AKI after endotoxin exposure. Anti-inflammatory signaling effects of IL-6 will be investigated in AKI-primed alveolar macrophages, in vivo and in vitro, by exposing alveolar macrophages to IL-6 in the setting of AKI and endotoxin. Tight junction protein loss and lung epithelial injury due to AKI-primed alveolar macrophages will be studied via targeted alveolar macrophage TNF-a inhibition or IL-6 administration. Methods to prevent bacterial translocation via targeted alveolar macrophage TNF-a inhibition or IT IL-6 will be studied. Bacterial translocation will be assessed by intravital confocal microscopy to track GFP-labeled Pseudomonas aeruginosa bacteria from the alveoli into the circulation. The experiments in this grant will provide useful leads into the development of interventions to prevent sepsis and improve survival in patients with AKI.

描述（适用提供）：急性肾脏损伤（AKI）很常见，并增加了死亡率。 AKI使多达20％的医院入院和30％至50％的ICU入院复杂化。 AKI诊断后，败血症发生在40-45％的患者中，并使死亡率增加一倍。无法治疗AKI或防止其并发症。迄今为止，对AKI疗法的基准研究的翻译已经完全不成功，因为所有检查在AKI患者中对动物模型有效的疗法进行了有效疗法的试验。已经提供了许多解释，对成功的最关键障碍有不同程度的一致性。在AKI社区中，一个值得注意的协议领域是，临床试验中的疗法是为时已晚，或者在AKI不适当阶段进行的疗法是有效的。在这笔赠款中，我们研究了Aki易屈服于肺炎败血症的机制。由于败血症发生在AKI诊断后发生（基于血清肌酐的AKI定义），因此我们认为这种并发症是高度适合预期和预防的。如果实现了该提案的目的，将确定改善AKI患者生存的立即适用目标。我们的总体假设是，在暴露于内毒素或革兰氏阴性细菌的情况下，AKI Primes肺泡巨噬细胞会发挥炎症反应。我们提出，旺盛的炎症反应介导肺部感染，紧密连接蛋白的丧失以及上皮通透性增加，这些通透性可将细菌的设施转移到循环中，从而导致细菌和败血症。我们有三个特定的目的：1）确定急性肾脏损伤（AKI）是否引起肺泡巨噬细胞的免疫原化； 2）确定Aki裂化的肺泡巨噬细胞是否介导肺上皮损伤； 3）确定Aki植入肺泡巨噬细胞中的肺上皮损伤是否会介导细菌在肺炎期间转化为循环。肺泡巨噬细胞的免疫启动将在体内确定，并在内毒素暴露后在AKI中产生过多的TNF-A产生。 IL-6的抗炎信号传导效应将在体内和体外的Aki植物肺泡巨噬细胞中研究，通过将肺泡巨噬细胞暴露于AKI和内毒素的环境中。将通过靶向的肺泡巨噬细胞TNF-A抑制或IL-6给药来研究由于Aki刺激的肺泡巨噬细胞引起的紧密连接蛋白丧失和肺上皮损伤。将研究通过靶向肺泡巨噬细胞TNF-A抑制或IL-6进行预防细菌易位的方法。细菌易位将通过插入共聚焦显微镜从肺泡中跟踪GFP标记的铜绿细菌到循环中。该赠款中的实验将为预防败血症和改善AKI患者的生存的干预措施提供有用的潜在客户。