Elevated Levels of Plasma TNF-α Are Associated With Microvascular Endothelial Dysfunction in Patients With Sepsis Through Activating the NF-κB and p38 Mitogen-Activated Protein Kinase in Endothelial Cells

Abstract

Inflammatory responses can induce microvascular and endothelial dysfunction, which is associated with the development of sepsis. This study is aimed at examining the concentrations of plasma tissue factor (TF), von Willebrand factor (vWF), and tumor necrosis factor-α (TNF-α) in patients with sepsis and at determining how septic plasma (SP) regulates TF and vWF expression and p38 mitogen activated protein kinase (p38 MAPK)/nuclear factor-κB (NF-κB) pathways in human endothelial cells. The concentrations of plasma TF, vWF, and TNF-α in 22 septic patients and eight healthy controls (HCs) were examined by enzyme-linked immunosorbent assay, and their potential association with disease severity was analyzed. Human umbilical vein endothelial cells (HUVECs) were treated with SP from patients or normal plasma (NP) from the HCs, and the levels of TF and vWF were measured. The SP-induced ERK, p38 MAPK, and NF-κB activation was characterized by Western blot and immunofluorescent assays. The SP-induced HUVEC apoptosis was detected by flow cytometry. The concentrations of plasma TF, vWF, and TNF-α in the patients were significantly higher than that in the HCs and were positively correlated with the Acute Physiology and Chronic Health Evaluation II scores in the patients. Furthermore, treatment with SP, but not NP, induced TF and vWF production in HUVECs in a dose- and time-dependent manner, which was associated with sequential activation of the p38 MAPK and NF-κB pathways. Septic plasma induced HUVEC apoptosis, which was inhibited by activating the NF-κB pathway. The sepsis-related inflammatory factors promoted endothelial cell activation, dysfunction, and apoptosis through activation of the p38 MAPK pathway that was regulated by NF-κB signaling.