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

Area of Science:

• Pulmonary medicine
• Molecular biology
• Cell biology

Background:

• Acute lung injury involves pulmonary endothelial barrier disruption, leading to lung edema.
• The molecular mechanisms underlying this barrier compromise are not fully understood.
• SOX18, a SOXF family member, protects endothelial barriers by upregulating CLDN5.

Purpose of the Study:

• To investigate the role of the SOX18-CLDN5 axis in LPS-induced pulmonary endothelial barrier disruption.
• To determine if SOX18 and CLDN5 expression is downregulated by LPS exposure.
• To elucidate the molecular mechanism of SOX18 downregulation by LPS.

Main Methods:

• In vivo LPS exposure models (intraperitoneal, intratracheal) in mice.
• In vitro studies using cultured human lung microvascular endothelial cells (HLMVECs) exposed to LPS.
• SOX18 overexpression and CLDN5 knockdown (siRNA) experiments.
• Analysis of SOX18 promoter activity and NF-κB binding.

Main Results:

• LPS exposure decreased SOX18 and CLDN5 expression in vivo and in vitro.
• SOX18 overexpression attenuated LPS-induced barrier disruption in HLMVECs and mouse lungs.
• Reduced CLDN5 expression diminished SOX18's barrier-protective effects.
• LPS-induced SOX18 downregulation resulted from NF-κB (p65) binding to the SOX18 promoter, with peroxynitrite mediating NF-κB activation.

Conclusions:

• NF-κB-dependent downregulation of the SOX18-CLDN5 axis is critical for LPS-induced pulmonary endothelial barrier disruption.
• This pathway is a key contributor to acute lung injury and edema.
• Targeting the SOX18-CLDN5 axis may offer therapeutic potential for acute lung injury.