Abstract
PurposeLeukocyte adhesion to vascular and matrix Metalloproteinase-8 (MMP8) expression is increased in sepsis and associated with poor prognosis in sepsis patients. This study aimed to investigate the role of MMP8 in sepsis serum mediated leukocyte adhesion.MethodsBioinformatics analysis of GSE64457 and GSE65682 was performed to evaluate the role of MMP8 in the progression of sepsis. Expression of MMP8 in blood samples from patients with sepsis was detected by qRT-PCR and ELISA. Human umbilical vein endothelial cells (HUVECs) were treated with sepsis serum, control serum, and MMP8 inhibitor. Expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) were detected by qRT-PCR and ELISA, respectively. The protein expression of total p38, phosphorylated-p38, ERK1/2, and p-ERK1/2 was detected by Western blotting. Peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) were incubated with the treated HUVECs to calculate leukocyte adhesion.ResultsFour hundred and twenty-nine differentially expressed genes (DEGs) and seven hub genes between sepsis patients and healthy controls were identified. GO function analysis of DEGs and hub genes indicated that the DEGs and hub genes were mainly enriched in neutrophil activation. MMP8 was selected as a key gene with an unfavorable prognosis in sepsis patients. The mRNA and protein expression of MMP8 in blood from sepsis patients were significantly higher than controls. Leukocyte adhesion and mRNA and protein expression of VCAM-1 and ICAM-1 were significantly increased in the sepsis serum group compared to that in the control group, as was the protein expression of p-p38 and p-ERK1/2. However, the MMP8 inhibitor suppressed the leukocyte adhesion promoted by sepsis serum by decreasing the expression of VCAM-1, ICAM-1, p-p38, and p-ERK1/2.ConclusionOur study indicated that MMP8 acts as a key gene in the development of sepsis, and sepsis serum promotes leukocyte adhesion to HUVECs via MMP8, which suggest that MMP8 might be a potential therapeutic target for sepsis.
Highlights
Sepsis, redefined in the Third International Consensus in 2016 as a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a complex clinical syndrome with extensive biochemical and physiological abnormalities [1]
The top 10 key genes were selected by three algorithms (MNC, MCC, and degree) in the cytoHubba plugin in Cytoscape and overlapped to identify the seven hub genes (MMP8, HP, ARG1, FOLR3, QSOX1, PGLYRP1, and OSCAR; Figures 1D,E)
Leukocyte adhesion to the vasculature and expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) are associated with the development of multiple organ failure in severe sepsis [25, 26]
Summary
Sepsis, redefined in the Third International Consensus in 2016 as a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a complex clinical syndrome with extensive biochemical and physiological abnormalities [1]. The Dysregulated innate and adaptive immune responses to infection play crucial roles in this syndrome [3]. Leukocytes are essential components of host immune cells in response to infection, and the recruitment, rolling, and adhesion of leukocytes to the endothelium are anomalously increased in sepsis [4, 5]. The endothelium is recognized as a key regulator of the early inflammatory response, including the recruitment, adhesion, and migration of leukocytes, and is considered a primary organ in the occurrence and development of sepsis [6, 7]. Leukocyte and endothelial dysfunction play a vital role in the pathophysiology of sepsis [8]
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