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（由申请人提供）：急性肾损伤 (AKI) 很常见，导致 40-45% 的 AKI 入院患者和 30% 至 50% 的 ICU 患者的死亡率增加。迄今为止，尚无治疗 AKI 或预防其并发症的疗法，将实验室研究转化为 AKI 疗法完全不成功，因为所有试验都检验了 AKI 疗法。对于 AKI 患者的动物模型是否有效，人们提出了许多解释，但对于 AKI 界最关键的障碍达成了不同程度的共识，即临床试验中的治疗也被采用。在 AKI 的晚期或不适当的阶段，为了有效，我们研究了 AKI 诱发肺炎败血症的机制，因为败血症发生在 AKI 诊断后（基于 AKI 的血清肌酐定义），我们相信这种并发症非常容易预测和预防，因此，如果该提案的目标得以实现，那么将确定一个立即适用的目标，以提高 AKI 患者的生存率。我们的总体假设是，AKI 会引发肺泡巨噬细胞产生旺盛的炎症。我们认为，当暴露于内毒素或革兰氏阴性细菌时，旺盛的炎症反应会介导肺部炎症、紧密连接蛋白的丧失以及上皮通透性的增加，从而促进细菌易位到循环中。我们有三个具体目标：1) 确定急性肾损伤 (AKI) 是否会导致肺泡巨噬细胞的免疫启动；2) 确定 AKI 启动的肺泡巨噬细胞是否介导肺上皮损伤；3) 确定 AKI 是否会导致肺上皮损伤； -引发的肺泡巨噬细胞在肺炎期间介导细菌易位到循环中。将通过内毒素暴露后 AKI 中过量的 TNF-α 产生来确定体内和体外巨噬细胞的情况。将在体内和体外研究 AKI 引发的肺泡巨噬细胞中 IL-6 的抗炎信号传导作用。将通过靶向研究在 AKI 和内毒素情况下肺泡巨噬细胞对 IL-6 的影响。肺泡巨噬细胞 TNF-a 抑制或 IL-6 给药将研究通过靶向肺泡巨噬细胞 TNF-a 抑制或 IT IL-6 来防止细菌移位。共聚焦显微镜追踪 GFP 标记的铜绿假单胞菌从肺泡进入循环系统，这项资助的实验将为开发预防脓毒症和提高 AKI 患者生存率的干预措施提供有用的线索。