Mechanisms of susceptibility to sepsis after acute kidney injury



 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.