LPS-induced Acute Lung Injury Involves NF-κB-mediated Downregulation of SOX18

Am J Respir Cell Mol Biol. 2018 May;58(5):614-624. doi: 10.1165/rcmb.2016-0390OC.


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-κB (p65) to a SOX18 promoter sequence located between -1,082 and -1,073 bp with peroxynitrite contributing to LPS-mediated NF-κB activation. We conclude that NF-κB-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / genetics
  • Acute Lung Injury / metabolism*
  • Acute Lung Injury / pathology
  • Animals
  • Binding Sites
  • Capillary Permeability*
  • Cells, Cultured
  • Claudin-5 / genetics
  • Claudin-5 / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Humans
  • Lipopolysaccharides*
  • Lung / blood supply*
  • Male
  • Mice, Inbred C57BL
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Peroxynitrous Acid / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Pulmonary Edema / chemically induced
  • Pulmonary Edema / genetics
  • Pulmonary Edema / metabolism*
  • Pulmonary Edema / pathology
  • SOXF Transcription Factors / genetics
  • SOXF Transcription Factors / metabolism*
  • Signal Transduction
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism


  • CLDN5 protein, human
  • Claudin-5
  • Cldn5 protein, mouse
  • Lipopolysaccharides
  • NF-kappa B
  • RELA protein, human
  • SOX18 protein, human
  • SOXF Transcription Factors
  • Sox18 protein, mouse
  • Transcription Factor RelA
  • Peroxynitrous Acid