Heparan sulfate acts in synergy with tight junction through STAT3 signaling to maintain the endothelial barrier and prevent lung injury development.

Summary

Across in vivo LPS lung injury and HUVEC models, preserving or supplementing glycocalyx heparan sulfate reduced tight junction damage and vascular leak by inhibiting STAT3 phosphorylation. Transcriptomics implicated STAT pathways, and STAT3 intervention ameliorated occludin/ZO-1 loss and permeability, positioning HS–STAT3 as a targetable axis to protect the endothelial barrier and limit pulmonary edema.

Key Findings

• LPS injury peaked at 6 h with maximal FITC-albumin leak, HS shedding, and occludin/ZO-1 impairment.
• Protecting HS or adding exogenous HS reduced tight junction damage and vascular permeability in HUVECs and mice.
• mRNA-seq implicated STAT pathways; inhibiting STAT3 phosphorylation ameliorated barrier defects.
• HS modulated tight junction proteins via STAT3, potentially through promoter binding of occludin and ZO-1.

Clinical Implications

Therapies that preserve the glycocalyx (e.g., HS mimetics) or modulate STAT3 may help maintain endothelial integrity and reduce pulmonary edema in ARDS. This supports translational testing of HS/STAT3-directed strategies.

Limitations

• Preclinical LPS models may not fully recapitulate human ARDS heterogeneity
• Direct STAT3 promoter binding evidence is suggestive rather than definitive

Future Directions

Test HS mimetics and STAT3 modulators in translational models and early-phase ARDS trials; validate HS–STAT3 signatures in patient endothelial/biomarker datasets.