Mechanisms of susceptibility to sepsis after acute kidney injury

急性肾损伤后脓毒症易感性机制

• 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
• 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

 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（阿基）很常见，并会增加死亡率。阿基使高达20%的住院和30%至50%的ICU住院复杂化。40-45%的患者在阿基诊断后发生脓毒症，死亡率加倍。没有治疗阿基或预防其并发症的疗法。迄今为止，将实验室研究转化为阿基治疗方法的工作完全不成功，因为所有在动物模型中有效的治疗方法在阿基患者中均失败。已经提出了许多解释，在成功的最关键障碍方面达成了不同程度的一致。阿基社区中一个值得注意的共识领域是，临床试验中的治疗给药太晚，或在阿基的不适当阶段，因此无效。在这项研究中，我们研究了阿基易患肺炎脓毒症的机制。由于脓毒症发生在阿基诊断后（基于阿基的血清肌酐定义），我们认为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，将确定一个立即适用的目标，以提高阿基患者的生存率。我们的总体假设是，阿基引发肺泡巨噬细胞在暴露于内毒素或革兰氏阴性细菌时产生旺盛的炎症反应。我们认为，旺盛的炎症反应介导肺部炎症，紧密连接蛋白的损失，并增加上皮细胞的通透性，促进细菌易位到循环中，导致菌血症和败血症。我们有三个具体目标：1）确定急性肾损伤（阿基）是否引起肺泡巨噬细胞的免疫致敏; 2）确定AKI致敏的肺泡巨噬细胞是否介导肺上皮损伤; 3）确定肺炎期间来自AKI致敏的肺泡巨噬细胞的肺上皮损伤是否介导细菌移位到循环中。肺泡巨噬细胞的免疫引发将在体内确定，并且在体外通过内毒素暴露后阿基中过量的TNF-α产生来判断。通过在阿基和内毒素的情况下将肺泡巨噬细胞暴露于IL-6，将在体内和体外研究IL-6在AKI致敏的肺泡巨噬细胞中的抗炎信号传导作用。将通过靶向肺泡巨噬细胞TNF-α抑制或IL-6给药研究由AKI引发的肺泡巨噬细胞引起的紧密连接蛋白损失和肺上皮损伤。将研究通过靶向肺泡巨噬细胞TNF-α抑制或IT IL-6来防止细菌移位的方法。将通过活体内检查评估细菌移位 共聚焦显微镜跟踪GFP标记的铜绿假单胞菌从肺泡进入循环。这项资助的实验将为开发预防脓毒症和改善阿基患者生存率的干预措施提供有用的线索。