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（由申请人证明）：急性肾脏损伤（AKI）是常见的，并增加了30％至50％的ICU入院。与住院医生相关的患者。由于对肺炎的肺炎的肺炎严重程度相似，但在AKI中，我们的肺炎具有更大的态度。革兰氏阴性细菌的免疫激活成分是炎症的，并以炎症的反应增加了假设是肺部发作的炎症反应，但我们提出了内毒素或埃里亚的肺部。 ）确定AKI是否引起肺免疫启动，2）在AKI中，AKI中的AKI中的细菌是否更大Akiwich中的重要因素会导致免疫启动（即能够的循环因子（使用腹膜透析）。在AIM 2中，我们试图估计细菌的易位易位，用插入的共核显微镜在AKI中解释了GFP-Labell Babelled Bacteria in Aki中的细菌，肺炎和AKI的活小鼠试图确定Aki刺激性肺泡的炎症反应通过降低正则表达并增加了肺部的渗透性，从而介导了肺炎。 AKI患者的顾客生存。