Resolving Endoplasmic Reticulum-Protein Misfolding Restores Corticosteroid Sensitivity in Experimental Models of Severe Asthma.

Summary

Endoplasmic reticulum stress impairs glucocorticoid receptor signaling and downregulates steroid-responsive genes, driving steroid resistance in severe asthma. The chemical chaperone 4-phenylbutyrate restored GR signaling and steroid responsiveness in human airway epithelial models and reduced airway inflammation and hyperresponsiveness in two steroid-resistant murine models.

Key Findings

• Chemical ER stress inducers downregulated HSD11B2 and FKBP5 and reduced GR nuclear translocation in human airway epithelial cells.
• TNF, IFN-γ, and IL-17 increased ER stress/protein misfolding markers and diminished dexamethasone-induced GR nuclear translocation.
• In severe asthma sputum cells, ER stress gene expression negatively correlated with GR signaling.
• 4-phenylbutyrate reversed cytokine-induced steroid resistance in differentiated primary bronchial epithelial cells.
• 4-phenylbutyrate plus dexamethasone reduced airway inflammation and/or hyperresponsiveness in two murine models of severe steroid-resistant asthma.

Clinical Implications

If validated clinically, ER stress markers could help identify steroid-resistant asthma endotypes and support add-on use of chemical chaperones (e.g., 4-PBA) to restore corticosteroid responsiveness.

Limitations

• Preclinical study; no randomized clinical trial data on 4-PBA in asthma
• Dosing, safety, and long-term effects of 4-PBA for airway disease remain untested clinically

Future Directions

Conduct biomarker-enriched early-phase trials of 4-PBA in severe steroid-resistant asthma, defining ER stress signatures, pharmacodynamics, and clinical efficacy/safety.