IL-33 facilitates endoplasmic reticulum stress and pyroptosis in LPS-stimulated ARDS model in vitro.

Summary

In LPS-stimulated hPMVECs, IL-33 heightened ER stress and pyroptosis and disrupted junctional proteins, worsening endothelial permeability. ER stress inhibition (4-PBA) and IL-33 neutralization restored junctional integrity and reduced inflammatory mediators; transcriptomic datasets and ARDS patient serum supported elevated IL-33.

Key Findings

• IL-33 expression was elevated in ARDS patient serum and across multiple GEO datasets (GSE237260, GSE216635, GSE89953, GSE263867, GSE5883) and correlated with clinical features.
• In LPS-stimulated hPMVECs, IL-33 enhanced ER stress markers (ATF6, IRE1a, p-ERK) and pyroptosis markers (NLRP3, IL-1β, IL-18) while disrupting junction proteins (Cx43, ZO-1).
• 4-PBA reduced permeability and IL-33 levels and increased connexins; IL-33 neutralizing antibody reversed ER stress/pyroptosis markers and restored junctional proteins.

Clinical Implications

Supports exploration of IL-33 blockade or ER stress modulators as adjunctive therapies to preserve endothelial integrity in ARDS.

Limitations

• In vitro endothelial model without animal validation
• LPS-induced model may not capture full complexity of human ARDS

Future Directions

Test IL-33 blockade in vivo ARDS models and evaluate biomarkers (e.g., IL-33, ER stress markers) in clinical cohorts to support translational development.