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

作者：Zhang, Hailing; Li, Jiehong; Wang, Xilong; Wang, Kai; Xie, Jianpeng; Chen, Guanjin; Li, Yijian; Zhong, Kai; Li, Jiahui; Chen, Xin^*

来源：PULMONARY PHARMACOLOGY & THERAPEUTICS, 2023, 83: 102263.

DOI：10.1016/j.pupt.2023.102263

• Acute lung injury
• IRE1 alpha/XBP1
• Airway epithelium
• beta-catenin

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. Inositolrequiring protein 1 alpha (IRE1 alpha)/X box protein-1 (XBP1) pathway was proved to regulate lipopolysaccharide (LPS)induced lung injury and inflammation. Yet, its role on epithelial beta-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 mu g/mL). Two selective antagonists of IRE1 alpha (4 mu 8c 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 downregulated total beta-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/beta-catenin signaling. Treatment with either 4 mu 8c or STF-083010 not only significantly attenuated LPSinduced lung injury and inflammation, but also recovered beta-catenin expression in airway epithelia, preserving the adhesive function of beta-catenin while blunting its signaling activity.Conclusion: These results illustrated that IRE1 alpha/XBP1 pathway promoted the activation of airway epithelial beta-catenin signaling in LPS-induced ALI.

• 单位
  南方医科大学