LIRAGLUTIDE ALLEVIATES ACUTE LUNG INJURY AND MORTALITY IN PNEUMONIA-INDUCED SEPSIS THROUGH REGULATING SURFACTANT PROTEIN EXPRESSION AND SECRETION

Abstract

Abstract Glucagon-like peptide-1 (GLP-1) analogs are used to treat type 2 diabetes (T2D), and they can regulate insulin secretion, energy homeostasis, inflammation and immune cell function. This study sought to determine if the GLP-1 analog Liraglutide exerts a beneficial action in an acute lung injury (ALI) model of pneumonia-induced sepsis. Methods Wild-type FVB/NJ mice (n = 114) were infected by intratracheal injection with Pseudomonas aeruginosa Xen5 (4x104 CFU/mouse) or an equal volume (50 μl) of saline (control) with or without a subcutaneous injection of Liraglutide (2 mg/kg, 30 min after infection). Mice were sacrificed 24 hours after infection. Lung tissues and BALF were analyzed. In separate experiments, the dynamic growth of bacteria and animal mortality were monitored using in vivo imaging system within 48 hours after infection. Additionally, primary lung alveolar type II (ATII) cells isolated from mice were used to study the mechanism of Liraglutide action. Result Liraglutide improved survival (P < 0.05), decreased bacterial loads in vivo and reduced lung injury scores (P < 0.01) in septic mice. Liraglutide-treated mice showed decreased levels of inflammatory cells (P < 0.01) and pro-inflammatory cytokines (TNF-α and IL-6) (P < 0.01) in the lung compared to septic controls. Liraglutide significantly increased pulmonary surfactant proteins (SP-A and SP-B) expression/secretion (P < 0.01) and phospholipid secretion (P < 0.01) in vivo. Primary ATII cells pretreated with Liraglutide improved SP-A and SP-B expression after LPS exposure (P < 0.01). Conclusion Liraglutide attenuates mortality and lung inflammation/injury in pneumonia-induced sepsis. The increased surfactant expression/secretion and anti-inflammatory effects of Liraglutide represent potential mechanisms by GLP-1 agonists potentiate host defense and maintain alveolar respiratory function in ALI.