CXCL13 Is Involved in the Lipopolysaccharide-Induced Hyperpermeability of Umbilical Vein Endothelial Cells
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ORIGINAL ARTICLE
CXCL13 Is Involved in the Lipopolysaccharide-Induced Hyperpermeability of Umbilical Vein Endothelial Cells Wen Chen,1 Yi Wang,2 Ting Zhou,2 Yuansheng Xu,2 Jianwei Zhan,2 and Jinhong Wu
2,3
Abstract— Sepsis is a disease that is characterized by a severe systemic inflammatory response
to microbial infection and lipopolysaccharide (LPS) and is a well-known inducer of sepsis, as well as endothelial cell hyperpermeability. In the present study, we confirm the elevation of CXC chemokine ligand 13 (CXCL13) in sepsis patients. We also show that LPS exposure increases the release of CXCL13, as well as the mRNA and protein expression of CXCL13 and its receptor, CXC chemokine receptor 5 (CXCR5) in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. We also examined the effects of CXCL13 knockdown on LPS-mediated endothelial hyperpermeability and tight junction (TJ) protein expression in HUVECs. Our results show that HUVECs exposed to LPS result in a significant decrease in transendothelial electrical resistance (TER) and TJ protein (Zonula occluden-1, occludin, and claudin-4) expression, and a notable increase in fluorescein isothiocyanate (FITC)-dextran flux and p38 phosphorylation, which was partially reversed by CXCL13 knockdown. Recombinant CXCL13 treatment had a similar effect as LPS exposure, which was attenuated by a p38 inhibitor, SB203580. Moreover, the CXCL13neutralizing antibody significantly increased the survival rate of LPS-induced sepsis mice. Collectively, our results show that CXCL13 plays a key role in LPS-induced endothelium hyperpermeability via regulating p38 signaling and suggests that therapeutically targeting CXCL13 may be beneficial for the treatment of sepsis. KEY WORDS: CXCL13; LPS; Permeability; p38.
Wen Chen and Yi Wang contributed equally to this work. 1
Department of General Practice, Hangzhou First People’s Hospital affiliated to Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 2 Department of Emergency, Hangzhou First People’s Hospital affiliated to Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 3 To whom correspondence should be addressed at Department of Emergency, Hangzhou First People’s Hospital affiliated to Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. E-mail: [email protected]
INTRODUCTION Sepsis is a disease characterized by a severe systemic inflammatory response to microbial infection [1]. The disease affects more than 18 million people every year [2], and despite intense efforts, poor prognosis is observed in patients with severe sepsis, with 40–60% a mortality rate [3, 4]. Most of the septic response is caused by endotoxin or lipopolysaccharide (LPS), the cell wall component of
0360-3997/20/0000-0001/0 # 2020 The Author(s)
Chen, Wang, Zhou, Xu, Zhan, and Wu bacteria. Microvascular dysfunction is regarded as a hallmark of sepsis [5]. Inflammatory mediators and free radicals, produced by the septic response, activate endothelial cells, which lead to endothelial da
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