Abstract
BackgroundEndothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits.MethodsPCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration.ResultsIn vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1.ConclusionPCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury.
Highlights
Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury
Protectin conjugates in tissue regeneration 1 (PCTR1) improves survival and lung function in mice after LPS administration We first determine the effect of PCTR1 on septic mice by survival curve analysis
There was no marked change in morphologic features in the LPS + PCTR1 group
Summary
Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Acute respiratory distress syndrome (ARDS), a severe sepsis complication, contributes to its high mortality [2]. Wang et al Respir Res (2021) 22:193 for sepsis-related lung injury [3,4,5]. The endothelial glycocalyx (EGL) primarily consists of glycosaminoglycans and proteoglycans, coating all healthy vascular endothelium [7]. Shedding of the endothelial glycocalyx is mainly driven by activation of heparan sulfate-specific heparanase, HPA [8]. Activated HPA promotes the degradation of the glycosaminoglycans and proteoglycans, and increases the level of glycocalyx components in the bloodstream, mainly including heparin sulphate (HS), hyaluronic acid (HA), and syndecan-1 (SDC-1) [8]. It is critical to improve glycocalyx reconstitution for the treatment of sepsis
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