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Acute Renal Failure Mediated Lung Injury

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Acute kidney injury (AKI) is a common complication in hospitalized patients that increases the risk of death. Death from AKI is typically due to systemic complications. Respiratory failure is an especially detrimental complication of AKI and increases patient mortality to 80%. The reason AKI causes respiratory failure is unclear, but may be due to inflammation. The systemic complications of AKI regarding the inflammatory cytokine IL-6 and lung injury are the focus of this grant proposal. We propose that AKI causes inflammation and lung injury. All studies will be completed in mice. We have three Specific Aims: 1) Determine the effect of AKI on proinflammatory cytokine production and cytokine clearance; 2) Determine the role of IL-6 in AKI mediated lung injury; 3) Determine if AKI exacerbates lung injury due to mechanical ventilation. Production of cytokines will be assessed in whole organs and serum of mice after AKI; renal cytokine clearance will be assessed by injection of recombinant forms of cytokines in mice with AKI and pharmacokinetic analysis of clearance will be performed. The effect of IL-6 on lung injury and KC (a mediator of neutrophil infiltration) will be tested IL-6 deficient and IL-6 inhibitor-treated mice with ischemic AKI or bilateral nephrectomy. Lung KC will be determined via mRNA and protein assessment of whole tissue homogenates; endothelial localization of KC will be determined via immunofluorescence. The injurious role of IL-6 and uremic factors will be assessed in vitro by adding recombinant IL-6 or uremic serum to cultured endothelial cells and assessing KC production, cell viability, and trans-endothelial resistance (a marker of capillary permeability and leak). To determine if the uremic factors that stimulate IL-6 production in AKI may be removed by dialysis, the effect of acute peritoneal dialysis on IL-6 production and serum IL-6 will be determined. Lung injury and alveolar macrophage KC production will be assessed in mice with or without mechanical ventilation in the presence or absence of AKI. Alveolar macrophage production of KC will be assessed by intracellular cytokine staining and flow cytometry of freshly isolated alveolar macrophages and by immunofluorescence. In vitro studies to assess the effect of IL-6 and uremic serum on KC production and cell viability of alveolar macrophages will be performed. The role of IL-6 in lung injury due to AKI with mechanical ventilation will be assessed using IL-6 deficient mice; the therapeutic benefit of IL-6 inhibition will be assessed by intraperitoneal or intratracheal administration of anti-IL-6 antibodies. The experiments in this grant will provide useful leads into the development of interventions to affect the systemic consequences of AKI and improve the mortality of patients with AKI.
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