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, and they can regulate insulin secretion, energy homeostasis, inflammation, and immune cell function. This study sought to determine whether the GLP-1 analog liraglutide exerts a beneficial action in an acute lung injury model of pneumonia-induced sepsis. Methods: Wild-type FVB/NJ mice (n = 114) were infected by intratracheal injection with Pseudomonas aeruginosa Xen5 (4 × 10 4 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 killed 24 h after infection. Lung tissues and BALF were analyzed. In separate experiments, the dynamic growth of bacteria and animal mortality was monitored using in vivo imaging system within 48 h after infection. In addition, primary lung alveolar type II 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 proinflammatory cytokines (TNF-α and IL-6) ( P < 0.01) in the lung compared with 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 alveolar type II 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 acute lung injury.