Vitamin D-VDR Signaling Modulates Epithelial-Driven Intra-Alveolar Coagulation via NF-κB in Sepsis-Associated ARDS

Area of Science:

• Pulmonary Medicine
• Endocrinology
• Critical Care

Background:

• Sepsis-associated acute respiratory distress syndrome (ARDS) involves excessive inflammation and intra-alveolar coagulation, impairing lung function.
• The role of vitamin D-vitamin D receptor (VDR) signaling in epithelial coagulation responses during ARDS is not fully understood.

Purpose of the Study:

• To investigate the regulatory role of vitamin D-VDR signaling in epithelial-driven intra-alveolar coagulation in sepsis-associated lung injury.

Main Methods:

• Utilized vitamin D-deficient mice, LPS-induced acute lung injury models, RLE-6TN alveolar epithelial cells, and clinical ARDS samples.
• Assessed expression of VDR, NF-κB p65, tissue factor (TF), and PAI-1 via qRT-PCR, Western blotting, ELISA, and immunohistochemistry.
• Conducted functional experiments including 1,25(OH)2D3 supplementation, VDR silencing, and NF-κB p65 gain/loss-of-function.

Main Results:

• Vitamin D deficiency exacerbated LPS-induced lung injury and intra-alveolar hypercoagulation, increasing TF and PAI-1.
• LPS challenge suppressed VDR and activated NF-κB signaling; 1,25(OH)2D3 supplementation restored VDR and attenuated TF/PAI-1.
• VDR silencing enhanced NF-κB activation and procoagulant responses; NF-κB p65 was essential for TF/PAI-1 upregulation.

Conclusions:

• Vitamin D-VDR signaling acts as a protective axis against NF-κB-driven epithelial procoagulant activation in sepsis-associated ARDS.
• Disruption of this pathway promotes intra-alveolar coagulation, suggesting vitamin D-VDR signaling restoration as a potential adjunctive therapy for ARDS.