Excessive and chronic airway inflammation associated with increased morbidity and mortality is a hallmark of cystic fibrosis (CF) airway disease. Previous studies underscored the role of endoplasmic reticulum (ER) signaling in CF airway inflammatory responses. In this review we discuss 1) how airway inflammation induces ER stress-triggered activation of the unfolded protein response and 2) the functional importance of the ER stress transducer inositol requiring enzyme 1α (IRE1α) in CF airway epithelial inflammatory responses. We also briefly review the current understanding of IRE1α activation and the development of small molecules aimed at modulating IRE1α kinase and RNase activities. Inhibition of IRE1α kinase and RNase may be considered as a novel therapeutic strategy to ameliorate the robust inflammatory status of CF airways.
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