Endoplasmic reticulum stress and the unfolded protein response in the pathogenesis of asthma

In this PhD thesis, we have comprehensively evaluated evidence of ER stress (ERS) and the Unfolded protein response (UPR) in asthma, how they associate with patient clinical information and its role in regulating antiviral, inflammatory and remodelling aspects of asthma. In the first chapter, we have systematically reviewed all related up-to-date literature and highlighted the knowleadge gap in the field of asthma research particularly ERS-UPR and asthma. In the second chapter, using two independent cohort studies, we have demonstrated robust evidence of ERS/UPR particularly in those patients with severe eosinophilic and neutrophilic inflammation that persist despite treatment with high dose corticosteroids. In the third chapter, we have evaluated how ERS/UPR regulates rhinovirus induced antiviral and inflammatory signaling in the airway epithelium using well-characterised ex-vivo primary bronchial epithelial cell (pBEC)-air-liquid interface (ALI) cultures. In the fourth chapter, we have demonstrated that ERS/UPR plays a key role in IL-13-driven epithelial remodelling, and leads to goblet cell hyperplasia, mucus hypersecretion and the release of profibrotic mediators. Inhibiting ERS using commercially available pharmaceuticals; 4-phenyl butyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA) significantly reduced these changes, while corticosteroids did not. Taken together, these findings demonstrate an unknown role of ERS/UPR in the pathogenesis of asthma and will lead us to investigate a novel therapeutic target for severe asthma.