[F31] Attenuation of sepsis-induced microvascular permeability and inflammation with the GLP-1R agonist liraglutide.

Ente: National Heart Lung and Blood Institute

Scadenza: 2028-05-31

Importo max: 38.298 EUR

Paese: US

Descrizione

Project Abstract Sepsis is a critical problem around the world causing 20% of all global deaths. The lack of effective therapeutics leaves critically ill patients with systemic organ dysfunction often caused by damage to the vascular endothelium. The damage induces micro-vessel dysfunction and increased permeability. Increased permeability can be attributed to tight junction and adherens junction disruption within endothelial cells. All blood vessels are lined with a single cell layer of endothelial cells that regulate exchanges between the bloodstream and the surrounding tissues and modulate inflammation. During sepsis, endothelial cells secrete circulating inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1) which cause upregulation of cell adhesion molecules that facilitate leukocyte trafficking and also MCP-1 also disrupts tight junctions in endothelial cells. Given the widespread vascular inflammation and breakdown of endothelial tight junctions in sepsis, therapeutic approaches to maintain and restore endothelial tight junctions is a compelling treatment strategy. GLP-1R agonists have unexpected anti-inflammatory and permeability attenuation effects. Preliminary in vitro studies suggest that the protective effects of the GLP-1R agonist, liraglutide, in sepsis are mediated through microvascular endothelium. Pre-treatment of primary human lung microvascular endothelial cells with liraglutide improved lipopolysaccharide-induced barrier dysfunction indicating important effects of liraglutide in protecting the endothelial barrier. In Aim 1, I will define the ability of liraglutide to attenuate microvascular permeability in vitro and in a clinically relevant murine model of polymicrobial abdominal sepsis. Additionally, in my preliminary studies, treatment of wild type mice with the GLP-1R agonist liraglutide significantly decreased plasma MCP-1, attenuated organ injury, and increased survival in a model of polymicrobial abdominal sepsis. MCP-1 secretion is regulated by p38 MAPK pathway activation. Interestingly, GLP-1R agonists regulate the activation of MAPK. Therefore, there is rationale that liraglutide inhibits MCP-1 secretion via MAPK regulation. MCP-1 attracts monocytes to the site of inflammation, but also promotes their adhesion by inducing them to upregulate ICAM-1 that is expressed in the activated endothelium. My preliminary data suggests that liraglutide decreases endothelial ICAM expression in vitro. These adhesion molecules allow the attachment of leukocytes to the endothelium and permit their transmigration into peripheral tissue. In Aim 2, I will define the mechanism by which Liraglutide restores the endothelial barrier through downregulation of MCP-1 and the subsequent leukocyte recruitment and tight junction and adherens junction stability. Completion of these aims will determine whether liraglutide attenuates sepsis-induced microvascular permeability and how liraglutide is vasculoprotective through an anti- Istituzione: VANDERBILT UNIVERSITY PI: David Aslaner Progetto: 5F31HL178162-02

Settori: National Heart Lung and Blood Institute

Vai al bando originale

Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.