11β-HSD1 may Aggravate Sepsis-associated Endothelial Dysfunction by Activating the NF-κB/MAPK Pathway and NLRP3...

Area of Science:

• Molecular Biology
• Immunology
• Pathophysiology

Background:

• Endothelial dysfunction significantly contributes to sepsis-related organ dysfunction.
• The precise molecular mechanisms driving sepsis-induced endothelial damage are not fully understood.

Purpose of the Study:

• To investigate the role of 11β-HSD1 in sepsis-induced endothelial dysfunction.
• To determine if 11β-HSD1 activates the NF-κB/MAPK pathway and NLRP3 inflammasome.

Main Methods:

• Utilized lipopolysaccharide (LPS)-stimulated human microvascular endothelial cells (HMEC-1) and a cecal ligation and puncture (CLP)-induced mouse model for in vitro and in vivo sepsis studies.
• Employed 11β-HSD1 inhibitor (BVT.2733), NLRP3 knockdown/knockout models, and assessed inflammatory cytokines, endothelial injury markers, and inflammasome activation via ELISA, qRT-PCR, Western blotting, immunofluorescence, and immunohistochemistry.
• Measured serum cortisol and NLRP3 levels in septic patients.

Main Results:

• Upregulated 11β-HSD1 expression in LPS-treated HMEC-1 cells and CLP-induced septic mouse aortic tissues.
• Observed decreased eNOS and VE-cadherin, increased inflammatory cytokines, and activated NF-κB/MAPK signaling and NLRP3 inflammasome.
• BVT.2733 treatment or NLRP3 blockade partially reversed these changes, attenuating endothelial damage; elevated serum cortisol and NLRP3 levels in septic patients, particularly non-survivors.

Conclusions:

• 11β-HSD1 appears to worsen sepsis-associated endothelial dysfunction by promoting NF-κB/MAPK signaling and NLRP3 inflammasome activation.
• Targeting the 11β-HSD1/NF-κB/MAPK/NLRP3 axis presents a potential therapeutic strategy for sepsis-related endothelial injury.
• Further studies are required to validate these findings.