Abstract
Vascular endothelial injury caused by post-hemorrhagic shock mesenteric lymph (PHSML) return is an important manifestation during refractory hemorrhagic shock. Using human umbilical vein endothelial cells (HUVECs) and transcriptome analysis, this study sought to investigate the molecular mechanism underlying the adverse effect of PHSML on vascular endothelium. Post-hemorrhagic shock mesenteric lymph was collected from male rats after they underwent hemorrhagic shock and following resuscitation, while normal mesenteric lymph (NML) was harvested from sham rats. Human umbilical vein endothelial cells were incubated with the culture medium containing either 10% phosphate buffered saline (Control), NML, or PHSML for 3 h, and then were harvested for RNA sequencing. In comparison with NML treated cells, 37 genes were differentially expressed in PHSML-treated HUVECs, including 32 upregulated genes and five downregulated genes. These differentially expressed genes were mainly enriched in inflammatory pathways, including signaling pathways for activation of the NOD-like receptors, NF-κB, and TNF. Furthermore, we found that C–C motif chemokine ligand 2 (CCL2) was increased significantly after PHSML treatment, and Bindarit, a CCL2 production inhibitor, attenuated the damage of HUVECs induced by PHSML. The results provide molecular evidence on vascular endothelium damage caused by PHSML. C–C motif chemokine ligand 2 might represent a new target for reducing vascular injury after severe hemorrhagic shock.
Highlights
Ischemic hypoxia, hyper-inflammation, and oxidative stress induced by hemorrhagic shock lead to the injury of vascular endothelial cells, which is the main cause of aggravating microcirculation dysfunction and organ injury following refractory hemorrhagic shock
These results indicated that normal mesenteric lymph (NML) had little effect on human umbilical vein endothelial cells (HUVECs), but post-hemorrhagic shock mesenteric lymph (PHSML) induced a significant change in gene expression pattern
In order to dissect the molecular mechanism of PHSML injury on endothelial cells, we performed RNA sequencing (RNA-seq) on HUVECs incubated with 10% phosphate buffered saline (PBS), 10% NML, and 10% PHSML, respectively
Summary
Hyper-inflammation, and oxidative stress induced by hemorrhagic shock lead to the injury of vascular endothelial cells, which is the main cause of aggravating microcirculation dysfunction and organ injury following refractory hemorrhagic shock. Numerous studies have shown that post-hemorrhagic shock mesenteric lymph (PHSML) return is the main cause of PHSML Induces Inflammation in HUVECs uncontrolled inflammation and acute distant organ damage [1,2,3]. One can study the pathophysiological mechanisms of cell injury and identify new targets for treatment and prevention of hemorrhagic shock. Human umbilical vein endothelial cell was mostly used to study vascular permeability and endothelial barrier function [8]. We sought to explore the mechanism of PHSML injury to vascular endothelium, HUVECs were incubated with PHSML and the differential mRNA expression was investigated using RNA sequencing (RNA-seq) technology. As a representative gene among differentially expressed genes, C–C motif chemokine ligand 2 (CCL2) and its inhibitor, Bindarit, were used to further confirm the roles of these genes in mediating HUVEC injury
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