Liraglutide as a Prophylactic Treatment for Sepsis Induced Lung Inflammation and Edema

Abstract

BackgroundThe severe lung dysfunction that characterizes acute respiratory distress syndrome is associated with excessive inflammation and edema. It occurs after an initiating insult to the lung, the most common of which being sepsis. As such, our research group has been investigating a glucagon‐like peptide‐1 (GLP‐1) receptor agonist, liraglutide, that inactivates NF‐κB, a transcription factor involved in the inflammatory response associated with sepsis.Hypothesisprophylactic treatment with liraglutide reduces lung inflammation and edema associated with a septic insult.MethodsWe pretreated C57/Bl6J mice two times a day with liraglutide (0.1mg/kg) or placebo (PBS) seven days prior to a two‐hit model of acute lung injury (cecal slurry induced polymicrobial abdominal sepsis and exposure to hyperoxia). To induce sepsis, an intraperitoneal injection of either 5% dextrose (control) or cecal slurry (2.4mg/g) was administered. Mice were then placed in a hyperoxia chamber (95%). At 6‐hours post cecal slurry injection mice were euthanized, a bronchoalveolar lavage (BAL) was performed, and lung tissue was collected. BAL was analyzed to measure protein content, leukocyte influx, and cell differentials. Wet‐dry ratios of lung tissue were also calculated.ResultsCompared to PBS and liraglutide treated sham mice, cecal slurry+hyperoxia caused an increase in markers of lung inflammation and edema. Septic mice pretreated with liraglutide had significantly decreased lung inflammation as measured the total number of inflammatory cells (2.2 vs 8.75 x 104 cells/ml; p<0.01; Figure 1) and neutrophils (0.33 vs 16.15 x 103 cells/ml; p<0.01) compared to untreated septic mice. Similarly, these septic mice also had significantly decreased lung edema as measured by wet‐dry ratios (4.15 vs 5.49; p<0.01) and protein content (285.52 vs 889.54 pg/ml; p<0.01).DiscussionThese results suggest that GLP‐1 receptor agonism attenuates sepsis and hyperoxia‐induced increases in lung inflammation and edema. Further, this data provides a strong rationale for additional studies, in other pre‐clinical models, to evaluate the potential of this receptor as a therapeutic target.