Abstract
Objective: Lipopolysaccharide (LPS) causes microvascular dysfunction, which is a key episode in the pathogenesis of endotoxemia. This work aimed to investigate the effect of Qing-Ying-Tang (QYT), a compound Chinese medicine in cerebral microcirculation disturbance and brain damage induced by LPS.Methods: Male C57/BL6 mice were continuously transfused with LPS (7.5 mg/kg/h) through the left femoral vein for 2 h. QYT (14.3 g/kg) was given orally 2 h after LPS administration. The dynamics of cerebral microcirculation were evaluated by intravital microscopy. Brain tissue edema was assessed by brain water content and Evans Blue leakage. Cytokines in plasma and brain were evaluated by flow cytometry. Confocal microscopy and Western blot were applied to detect the expression of junction and adhesion proteins, and signaling proteins concerned in mouse brain tissue.Results: Post-treatment with QYT significantly ameliorated LPS-induced leukocyte adhesion to microvascular wall and albumin leakage from cerebral venules and brain tissue edema, attenuated the increase of MCP-1, MIP-1α, IL-1α, IL-6, and VCAM-1 in brain tissue and the activation of NF-κB and expression of MMP-9 in brain. QYT ameliorated the downregulation of claudin-5, occludin, JAM-1, ZO-1, collagen IV as well as the expression and phosphorylation of VE-cadherin in mouse brain.Conclusions: This study demonstrated that QYT protected cerebral microvascular barrier from disruption after LPS by acting on the transcellular pathway mediated by caveolae and paracellular pathway mediated by junction proteins. This result suggests QYT as a potential strategy to deal with endotoxemia.
Highlights
Lipopolysaccharide (LPS) causes endotoxemia and sepsis, leading to multiple organ failure and infectious shock resulting in a range of disastrous sequels (Berger et al, 2017)
LPS binds to toll like receptor 4 (TLR-4) (Tsukamoto et al, 2018) and activates nuclear transcription factor κB (NF-κB), causing the release of inflammatory factors and the expression of chemotactic molecules and adhesion molecules, promoting the recruitment of leukocytes in venules (Bienvenu and Granger, 1993; Khakpour et al, 2015), resulting in microvascular occlusion and tissue ischemia (Cohen, 2002)
LPS recognized by TLR4 activates Src family protein tyrosine kinases (Plociennikowska et al, 2015), which in turn induces NF-κB translocation or directly activates Rock kinase and myosin light chain kinase (MLCK) signaling that causes disruption of endothelial cell junctions (Clark et al, 2015) and impairs integrity of vascular basement membrane, resulting in hyperpermeability, hemorrhage and thrombosis (Mombouli and Vanhoutte, 1999), which eventually lead to multiple organ failure, septic shock and even death (Khakpour et al, 2015)
Summary
Lipopolysaccharide (LPS) causes endotoxemia and sepsis, leading to multiple organ failure and infectious shock resulting in a range of disastrous sequels (Berger et al, 2017). LPS recognized by TLR4 activates Src family protein tyrosine kinases (Plociennikowska et al, 2015), which in turn induces NF-κB translocation or directly activates Rock kinase and myosin light chain kinase (MLCK) signaling that causes disruption of endothelial cell junctions (Clark et al, 2015) and impairs integrity of vascular basement membrane, resulting in hyperpermeability, hemorrhage and thrombosis (Mombouli and Vanhoutte, 1999), which eventually lead to multiple organ failure, septic shock and even death (Khakpour et al, 2015). Ameliorating microvascular hyperpermeability and edema is anticipated as an important treatment strategy
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
