Liraglutide Pretreatment Attenuates Sepsis-Induced Acute Lung Injury.

There are no effective targeted therapies to treat acute respiratory distress syndrome (ARDS). Recently, the commonly used diabetes and obesity medications, glucagon-like peptide-1 (GLP-1) receptor agonists, have been found to have anti-inflammatory properties. We therefore hypothesized that liraglutide pretreatment would attenuate murine sepsis-induced acute lung injury (ALI). We used a two-hit model of ALI (sepsis+hyperoxia). Sepsis was induced by intraperitoneal injection of cecal slurry (CS;2.4mg/g) or 5% dextrose (control) followed by hyperoxia (HO;FiO=0.95) or room air (control,FiO=0.21). Mice were pre-treated twice daily with subcutaneous injections of liraglutide (0.1mg/kg) or saline for 3-days prior to initiation of CS+HO. At 24-hours post-CS+HO, physiologic dysfunction was measured by weight loss, severity of illness score, and survival. Animals were sacrificed, and bronchoalveolar lavage (BAL) fluid, lung and spleen tissue were collected. Bacterial burden was assessed in the lung and spleen. Lung inflammation was assessed by BAL inflammatory cell numbers, cytokine concentrations, lung tissue myeloperoxidase activity and cytokine expression. Disruption of the alveolar-capillary barrier was measured by lung wet-to-dry weight ratios, BAL protein, and epithelial injury markers (receptor for advanced glycation end products and sulfated glycosaminoglycans). Histologic evidence of lung injury was quantified using a five-point score with four parameters: inflammation, edema, septal thickening, and RBCs in the alveolar space. Compared to saline treatment, liraglutide improved sepsis-induced physiologic dysfunction and reduced lung inflammation, alveolar-capillary barrier disruption, and lung injury, GLP-1 receptor activation may hold promise as a novel treatment strategy for sepsis-induced ARDS. Additional studies are needed to better elucidate its mechanism of action.