The role of acute kidney in the pathogenesis of sepsis from pneumonia

急性肾在肺炎脓毒症发病机制中的作用

• 批准号: 9003708
• 负责人: Sarah g Faubel
• 金额: $ 31.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9003708
• 关键词: Acute; Acute Lung Injury; Acute Renal Failure with Renal Papillary Necrosis; Admission activity; Affect; Alveolar Macrophages; Bacteremia; Bacteria; Bacterial Counts; Bacterial Translocation; Blood; Blood Circulation; Breathing; Bronchoalveolar Lavage Fluid; CXCL1 gene; Cessation of life; Complication; Confocal Microscopy; Data; Diagnosis; Dialysis procedure; Endotoxins; Epithelial; Genes; Gram-Negative Bacteria; Grant; Hospitals; Hour; Immune; Immune response; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Response; Intensive Care Units; Intervention; Intestines; Kidney; Label; Lead; Life; Lung; Lung Inflammation; Maintenance; Measures; Mediating; Mus; Neutrophil Infiltration; Nosocomial pneumonia; Pathogenesis; Patients; Peritoneal Dialysis; Permeability; Pneumonia; Production; Proteins; Pseudomonas; Pseudomonas aeruginosa; Risk Factors; Role; Sepsis; Severities; TNF gene; Tight Junctions; cell type; chemokine; claudin 4; clinically relevant; immune function; immunosuppressed; improved; lung injury; mortality; neutrophil; novel; prevent; public health relevance; research study; response; septic; therapy development

 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. Pneumonia is the most common cause of sepsis and infection-related death in hospitalized patients. Mortality in pneumonia doubles when patients become bacteremic. Since the vast majority of patients with bacteremia are septic, bacteremia may be considered equivalent to sepsis. In this grant, we investigate the mechanisms by which AKI predisposes to bacteremia and sepsis from pneumonia. The mechanism by which pneumonia causes bacteremia is poorly understood and is generally considered to be due to immunosuppression leading to overwhelming of lung bacterial defenses. In preliminary studies, we found that mice with AKI had similar pneumonia severity to controls with pneumonia, yet bacteremia was greater in AKI. Thus, immunosuppression does not explain bacteremia during AKI. In fact, rather than an immunosuppressed response, our preliminary studies demonstrate that the response to endotoxin (the immune activating component of gram negative bacteria) was exuberant and characterized by an increased inflammatory response. Claudin 4, a lung epithelial tight junction protein, was reduced suggesting that increased epithelial permeability was present in AKI with pneumonia. Thus, we suggest that AKI causes immune priming, not immunosuppression, of the lung. Preliminary studies suggest the lung immune priming in AKI coincides with lung neutrophil recruitment. Our overall hypothesis is that AKI primes the lung to exert an exuberant inflammatory response when exposed to endotoxin or pneumonia from gram negative bacteria. We propose that the exuberant inflammatory response mediates lung inflammation, loss of tight junction proteins (e.g., claudin 4), 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 AKI causes lung immune priming, 2) Determine if bacterial translocation is greater in AKI with pneumonia, 3 Determine if loss of claudin 4 mediates bacterial translocation in AKI with pneumonia. In Aim 1, we seek to characterize the immune primed response, determine if this response is specific to alveolar macrophages, and identify factors in AKI which lead to immune priming (i.e., neutrophil recruitment and dialyzable circulating factors (using peritoneal dialysis). In Aim 2, we seek to establish that increased translocation of bacteria explains bacteremia in AKI using intravital confocal microscopy to track and quantify translocation of GFP-labelled bacteria in live mice with pneumonia and AKI. In Aim three, we seek to establish that the inflammatory response of AKI-primed alveolar macrophages mediates bacteremia during pneumonia by down regulating claudin 4 expression and increasing lung epithelial permeability. The experiments in this grant will provide useful leads into the development of interventions to prevent sepsis from pneumonia and improve survival in patients with AKI.

 描述(由申请人提供)：急性肾损伤(AKI)很常见，会增加死亡率。AKI使高达20%的医院入院和30%至50%的ICU入院复杂化。AKI确诊后，40%-45%的患者会发生脓毒症，并使死亡率翻一番。肺炎是导致住院患者败血症和感染相关死亡的最常见原因。当患者出现细菌血症时，肺炎的死亡率会增加一倍。由于绝大多数菌血症患者是败血症，菌血症可被认为等同于败血症。在这项资助中，我们调查了AKI导致肺炎菌血症和败血症的机制。肺炎引起菌血症的机制尚不清楚，通常被认为是由于免疫抑制导致肺部细菌防御系统的压倒。在初步研究中，我们发现AKI组小鼠的肺炎严重程度与肺炎对照组相似，但AKI组的菌血症更严重。因此，免疫抑制不能解释急性心肌梗死期间的菌血症。事实上，我们的初步研究表明，对内毒素(革兰氏阴性细菌的免疫激活成分)的反应是活跃的，并以炎症反应增加为特征，而不是免疫抑制反应。肺上皮紧密连接蛋白Claudin 4表达降低，提示AKI合并肺炎时上皮通透性增加。因此，我们认为AKI引起了肺的免疫启动，而不是免疫抑制。初步研究表明，AKI的肺免疫启动与肺中性粒细胞募集相一致。我们的总体假设是，AKI使肺部在暴露于内毒素或革兰氏阴性细菌肺炎时产生旺盛的炎症反应。我们认为，活跃的炎症反应介导了肺部炎症，紧密连接蛋白(如claudin 4)的丢失，以及上皮通透性的增加，这有助于细菌移位到循环中，导致菌血症和败血症。我们有三个具体的目标：1)确定AKI是否引起肺免疫启动；2)确定AKI合并肺炎时细菌移位是否更大；3确定Claudin 4丢失是否介导了AKI合并肺炎时的细菌移位。在目标1中，我们试图描述免疫启动反应的特征，确定这种反应是否是肺泡巨噬细胞所特有的，并确定AKI中导致免疫启动的因素(即，中性粒细胞募集和可透析的循环因子(使用腹膜透析))。在目标2中，我们试图利用活体共聚焦显微镜来跟踪和量化肺炎和AKI活体小鼠中GFP标记的细菌的易位，以确定细菌易位增加可以解释AKI中的菌血症。在第三个目标中，我们试图证明AKI诱导的肺泡巨噬细胞的炎症反应通过下调claudin 4的表达和增加肺上皮通透性来介导肺炎期间的菌血症。这笔赠款中的实验将为开发干预措施以预防肺炎败血症和提高AKI患者的存活率提供有用的指导。