Liraglutide protects against microvascular dysfunction and sepsis-mediated inflammation and organ injury

Introduction: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection characterized by increased systemic inflammation and microvascular injury. Recently, commonly used diabetes and obesity medications, glucagon-like peptide-1 (GLP-1) receptor agonists, have demonstrated unexpected anti-inflammatory effects. We tested GLP-1 receptor agonist liraglutide in a clinically relevant two-hit murine model of polymicrobial abdominal sepsis and hyperoxia and microvascular endothelial injury in vitro, hypothesizing that GLP-1 receptor agonists exert protective effects during sepsis, limiting microvascular permeability, inflammation, organ injury and death. Methods: Sepsis was induced in male and female mice by intraperitoneal (IP) injection of cecal contents (CS;1.8 mg/g body weight) collected from euthanized donor mice. Mice were also exposed to hyperoxia (FiO 2 90-96%) for 24 hours. Six and 18 hours after CS injection, mice were administered saline or liraglutide (0.1 mg/kg). At 12 hours, mice were given fluids and antibiotics. At 24 hours, mice were euthanized for plasma and bronchoalveolar lavage (BAL; right lung) collection. Plasma cytokines, organ injury markers, and BAL immune cells and protein were measured. The left lung was tied off and excised to measure wet-to-dry lung weight ratios. Additionally, for in vitro studies, primary human lung microvascular endothelial cells (HLMVECs) were treated with saline or liraglutide for 24 hours prior to saline (control) or LPS (100 ng/mL). HLMVEC barrier dysfunction was quantified using express permeability testing (XPerT) assay or Electric Cell-Substrate Impedance Sensing (ECIS) to measure transendothelial electrical resistance (TER). Results: In murine sepsis, illness severity scores and lung injury were improved in mice pretreated with liraglutide (N=12). Plasma blood urea nitrogen (BUN; P=0.0581), alanine transaminase (ALT; P=0.0311) and aspartate aminotransferase (AST; P=0.0263), and cytokines IL-1β (P=0.0078), IL-6 (P=0.0038), and TNF-α (P=0.0183) in plasma were reduced in mice treated with liraglutide. In HLMVECs, liraglutide (1.5 nM) significantly reduced LPS-induced barrier dysfunction measured by XPerT assay (P=0.0030) and ECIS (P=0.0075). Conclusion: Liraglutide reduces illness severity, inflammation, and organ injury in a two-hit model of sepsis-induced ALI. Liraglutide has direct effects in the microvascular endothelium, limiting LPS-mediated barrier dysfunction. These findings support a protective role for GLP-1 receptor agonism in sepsis, mediated through the microvasculature. HL150783, AG075341, HL158906. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.