IRE1α/XBP-1 promotes ß-catenin signaling activation of airway epithelium in lipopolysaccharide-induced acute lung injury.

ABSTRACT

BACKGROUND: Acute lung injury (ALI), along with the more severe condition--acute respiratory distress syndrome (ARDS), is a major cause of respiratory failure in critically ill patients with high morbidity and mortality. Inositol-requiring protein 1α (IRE1α)/X box protein-1 (XBP1) pathway was proved to regulate lipopolysaccharide (LPS)-induced lung injury and inflammation. Yet, its role on epithelial ß-catenin in LPS-induced ALI remains to be elucidated. METHODS: LPS-induced models were generated in mice (5 mg/kg) and Beas-2B cells (200 µg/mL). Two selective antagonists of IRE1α (4µ8c and STF-083010) were respectively given to LPS-exposed mice and cultured cells. RESULTS: Up-regulated expression of endoplasmic reticulum (ER) stress markers immunoglobulin-binding protein (BIP) and spliced X box protein-1(XBP-1s) was detected after LPS exposure. Besides, LPS also led to a down-regulated total ß-catenin level in the lung and Beas-2B cells, with decreased membrane distribution as well as increased cytoplasmic and nuclear accumulation, paralleled by extensively up-regulated downstream targets of the Wnt/ß-catenin signaling. Treatment with either 4µ8c or STF-083010 not only significantly attenuated LPS-induced lung injury and inflammation, but also recovered ß-catenin expression in airway epithelia, preserving the adhesive function of ß-catenin while blunting its signaling activity. CONCLUSION: These results illustrated that IRE1α/XBP1 pathway promoted the activation of airway epithelial ß-catenin signaling in LPS-induced ALI.