Differential involvement of sulodexide in lipopolysaccharide- and pneumolysin-induced lung endothelial barrier dysfunction in vitro and in vivo

Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are defined by impairment of the pulmonary endothelial barrier, resulting in vascular permeability and pulmonary edema. Toxins such as lipopolysaccharide (LPS) from Gram positive bacteria and pneumolysin (PLY) from Gram negative bacteria contribute to endothelial injury by impairing the glycocalyx and intercellular connections. This study investigated the protective effects of sulodexide (SDX), a glycocalyx-preserving agent, against LPS- and PLY-induced endothelial barrier dysfunction in human lung microvascular endothelial cells (HLMVECs) and murine ALI models. Endothelial barrier integrity was evaluated using transendothelial electrical resistance (TER), junctional integrity by immunofluorescence staining for VE-cadherin and F-actin, and lung vascular leak by Evans Blue Dye (EBD) assay, and protein content by bronchoalveolar lavage fluid (BALF). Pretreatment with SDX mitigated PLY's effects on TER, junctional integrity, and in vivo vascular leak, and post-treatment with SDX restored TER after PLY insult. SDX's effects on LPS-induced TER decline and lung permeability, while significant, were less pronounced. These findings suggest SDX protects lung endothelial barrier integrity in vitro and in vivo in a toxin-specific manner, with more evident protection against pore-forming toxins like PLY than against receptor-mediated toxins like LPS. SDX may represent a therapeutic strategy for preventing vascular leakage and lung injury in Gram-positive bacterial infections and inflammatory lung disease.