TY - JOUR
T1 - LPS-induced acute lung injury involves NF-kB–mediated downregulation of SOX18
AU - Gross, Christine M.
AU - Kellner, Manuela
AU - Wang, Ting
AU - Lu, Qing
AU - Sun, Xutong
AU - Zemskov, Evgeny A.
AU - Noonepalle, Satish
AU - Kangath, Archana
AU - Kumar, Sanjiv
AU - Gonzalez-Garay, Manuel
AU - Desai, Ankit
AU - Aggarwal, Saurabh
AU - Gorshkov, Boris
AU - Klinger, Christina
AU - Verin, Alexander D.
AU - Catravas, John D.
AU - Jacobson, Jeffrey R.
AU - Yuan, Jason X.J.
AU - Rafikov, Ruslan
AU - Garcia, Joe G.N.
AU - Black, Stephen M.
N1 - Funding Information:
Supported in part by grants HL60190 (S.M.B.), HL67841 (S.M.B.), HL101902 (S.M.B.), P01HL134610 (S.M.B.), HL126609 (J.G.N.G.), HL115014 (J.X.-J.Y.), HL096887 (J.R.J.), and HL132918 (R.R.), all from the National Institutes of Health (NIH), and by a Scientist Development Grant (14SDG20480354 [R.R.]) from the American Heart Association National Office.
Publisher Copyright:
Copyright © 2018 by the American Thoracic Society.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - One of the early events in the progression of LPS-mediated acute lung injury in mice is the disruption of the pulmonary endothelial barrier resulting in lung edema. However, the molecular mechanisms by which the endothelial barrier becomes compromised remain unresolved. The SRY (sex-determining region on the Y chromosome)–related high-mobility group box (Sox) group F family member, SOX18, is a barrier-protective protein through its ability to increase the expression of the tight junction protein CLDN5. Thus, the purpose of this study was to determine if downregulation of the SOX18-CLDN5 axis plays a role in the pulmonary endothelial barrier disruption associated with LPS exposure. Our data indicate that both SOX18 and CLDN5 expression is decreased in two models of in vivo LPS exposure (intraperitoneal, intratracheal). A similar downregulation was observed in cultured human lung microvascular endothelial cells (HLMVECs) exposed to LPS. SOX18 overexpression in HLMVECs or in the mouse lung attenuated the LPS-mediated vascular barrier disruption. Conversely, reduced CLDN5 expression (siRNA) reduced the HLMVEC barrier-protective effects of SOX18 overexpression. The mechanism by which LPS decreases SOX18 expression was identified as transcriptional repression through binding of NF-kB (p65) to a SOX18 promoter sequence located between 21,082 and 21,073 bp with peroxynitrite contributing to LPS-mediated NF-kB activation. We conclude that NF-kB–dependent decreases in the SOX18-CLDN5 axis are essentially involved in the disruption of human endothelial cell barrier integrity associated with LPS-mediated acute lung injury.
AB - One of the early events in the progression of LPS-mediated acute lung injury in mice is the disruption of the pulmonary endothelial barrier resulting in lung edema. However, the molecular mechanisms by which the endothelial barrier becomes compromised remain unresolved. The SRY (sex-determining region on the Y chromosome)–related high-mobility group box (Sox) group F family member, SOX18, is a barrier-protective protein through its ability to increase the expression of the tight junction protein CLDN5. Thus, the purpose of this study was to determine if downregulation of the SOX18-CLDN5 axis plays a role in the pulmonary endothelial barrier disruption associated with LPS exposure. Our data indicate that both SOX18 and CLDN5 expression is decreased in two models of in vivo LPS exposure (intraperitoneal, intratracheal). A similar downregulation was observed in cultured human lung microvascular endothelial cells (HLMVECs) exposed to LPS. SOX18 overexpression in HLMVECs or in the mouse lung attenuated the LPS-mediated vascular barrier disruption. Conversely, reduced CLDN5 expression (siRNA) reduced the HLMVEC barrier-protective effects of SOX18 overexpression. The mechanism by which LPS decreases SOX18 expression was identified as transcriptional repression through binding of NF-kB (p65) to a SOX18 promoter sequence located between 21,082 and 21,073 bp with peroxynitrite contributing to LPS-mediated NF-kB activation. We conclude that NF-kB–dependent decreases in the SOX18-CLDN5 axis are essentially involved in the disruption of human endothelial cell barrier integrity associated with LPS-mediated acute lung injury.
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U2 - 10.1165/rcmb.2016-0390OC
DO - 10.1165/rcmb.2016-0390OC
M3 - Article
C2 - 29115856
AN - SCOPUS:85046695017
VL - 58
SP - 614
EP - 624
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 5
ER -