LPS-induced acute lung injury involves NF-kB–mediated downregulation of SOX18

Christine M. Gross, Manuela Kellner, Ting Wang, Qing Lu, Xutong Sun, Evgeny A. Zemskov, Satish Noonepalle, Archana Kangath, Sanjiv Kumar, Manuel Gonzalez-Garay, Ankit A. Desai, Saurabh Aggarwal, Boris Gorshkov, Christina Klinger, Alexander D. Verin, John D. Catravas, Jeffrey R. Jacobson, Jason X.J. Yuan, Ruslan Rafikov, Joe G.N. GarciaStephen M. Black

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)614-624
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume58
Issue number5
DOIs
StatePublished - May 1 2018

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Acute Lung Injury
Endothelial cells
Down-Regulation
Lung
NF-kappa B
Endothelial Cells
Tight Junction Proteins
Peroxynitrous Acid
Chromosomes
Small Interfering RNA
Chemical activation
Aptitude
Y Chromosome
Blood Vessels
Edema
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

LPS-induced acute lung injury involves NF-kB–mediated downregulation of SOX18. / Gross, Christine M.; Kellner, Manuela; Wang, Ting; Lu, Qing; Sun, Xutong; Zemskov, Evgeny A.; Noonepalle, Satish; Kangath, Archana; Kumar, Sanjiv; Gonzalez-Garay, Manuel; Desai, Ankit A.; Aggarwal, Saurabh; Gorshkov, Boris; Klinger, Christina; Verin, Alexander D.; Catravas, John D.; Jacobson, Jeffrey R.; Yuan, Jason X.J.; Rafikov, Ruslan; Garcia, Joe G.N.; Black, Stephen M.

In: American journal of respiratory cell and molecular biology, Vol. 58, No. 5, 01.05.2018, p. 614-624.

Research output: Contribution to journalArticle

Gross, CM, Kellner, M, Wang, T, Lu, Q, Sun, X, Zemskov, EA, Noonepalle, S, Kangath, A, Kumar, S, Gonzalez-Garay, M, Desai, AA, Aggarwal, S, Gorshkov, B, Klinger, C, Verin, AD, Catravas, JD, Jacobson, JR, Yuan, JXJ, Rafikov, R, Garcia, JGN & Black, SM 2018, 'LPS-induced acute lung injury involves NF-kB–mediated downregulation of SOX18', American journal of respiratory cell and molecular biology, vol. 58, no. 5, pp. 614-624. https://doi.org/10.1165/rcmb.2016-0390OC
Gross, Christine M. ; Kellner, Manuela ; Wang, Ting ; Lu, Qing ; Sun, Xutong ; Zemskov, Evgeny A. ; Noonepalle, Satish ; Kangath, Archana ; Kumar, Sanjiv ; Gonzalez-Garay, Manuel ; Desai, Ankit A. ; Aggarwal, Saurabh ; Gorshkov, Boris ; Klinger, Christina ; Verin, Alexander D. ; Catravas, John D. ; Jacobson, Jeffrey R. ; Yuan, Jason X.J. ; Rafikov, Ruslan ; Garcia, Joe G.N. ; Black, Stephen M. / LPS-induced acute lung injury involves NF-kB–mediated downregulation of SOX18. In: American journal of respiratory cell and molecular biology. 2018 ; Vol. 58, No. 5. pp. 614-624.
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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 A.

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.

PY - 2018/5/1

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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.

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