title: 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.
authors.affiliation: Department of Intensive Care Unit, The First Affiliated Hospital, China Medical University, Liaoning Province, China.
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Liang
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Yini
authors.initials: Y
authors.lastname: Sun
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liu
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Ma
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D018805:Sepsis / Q000097:blood* / Q000503:physiopathology; D013925:Thromboplastin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D013925:Thromboplastin; D048051:p38 Mitogen-Activated Protein Kinases