Abstract
Lipopolysaccharide (LPS) can lead to vascular endothelial barrier dysfunction, which often results in acute lung injury and acute respiratory distress syndrome. However, the effects of different concentrations of LPS on human pulmonary microvascular endothelial barrier function and the involvement of the phosphatidylinositol-3-kinase-serine/threonine kinase (PI3K/Akt) pathway in this process remain unclear. Human pulmonary microvascular endothelial cells (HPMECs) were stimulated with different doses of LPS, and barrier function was examined by determining cell monolayer permeability, cell migration, and the expression of intercellular junction proteins (VE-Cadherin, Claudin-5, and Connexin-43). LY294002 was used to inhibit PI3K to verify the role of the PI3K/Akt pathway in the regulation of barrier function in HPMECs stimulated by LPS. Low doses of LPS increased HPMEC migration, up-regulated VE-Cadherin and Claudin-5 expression, down-regulated Connexin-43 expression, and promoted Akt phosphorylation, which could collectively decrease monolayer permeability. In contrast, high doses of LPS suppressed HPMEC migration, down-regulated the expression of VE-Cadherin and Claudin-5, up-regulated Connexin-43 expression, and reduced Akt phosphorylation, which could collectively increase monolayer permeability. LPS has a biphasic effect on HPMEC barrier function through the PI3K/Akt pathway, and this effect is concentration-dependent.
Highlights
Sepsis is a life-threatening condition resulting from organ dysfunction due to a dysregulated host response to infection[1]
There was no significant difference between Evans Blue (EB) concentrations in the 1 μg/ml LPS group and the control group (Fig. 1B)
In a study on atherosclerosis, a chronic inflammatory disease of vessels, endothelial cell migration was shown to be involved in neovascularization and caused the plaques to become vulnerable to rupture[17]
Summary
Sepsis is a life-threatening condition resulting from organ dysfunction due to a dysregulated host response to infection[1]. It is one of the major causes of death in critically ill patients[2]. To investigate the differences of clinical severity in ALI and ARDS, we examined the effect of different concentrations of LPS on HPMECs. Previous studies have shown that the cell-cell junction formation, cell migration and cell proliferation changes associated with endothelial barrier dysfunction, are mediated by the PI3K/Akt pathway[8,9,10]. The PI3K/Akt pathway is the main regulator of endothelial barrier function in HPMECs6. This study investigated whether HPMECs treated with different concentrations of LPS displayed different levels of barrier dysfunction induced by signal cascade activation
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