Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor κB activation

Abstract

Background: Despite many studies on endoplasmic reticulum (ER) stress in patients with various inflammatory diseases, there is scarce information on ER stress in patients with bronchial asthma.

Objective: In this study we aimed to elucidate the role of ER stress in the pathogenesis of bronchial asthma.

Methods: Using mice sensitized with ovalbumin (OVA) and LPS and challenged with OVA (OVA(LPS)-OVA mice), as well as mice sensitized and challenged with OVA (OVA-OVA mice), we investigated whether ER stress is involved in the pathogenesis of bronchial asthma. Moreover, we also determined the levels of ER stress markers in blood and bronchoalveolar lavage fluid from asthmatic patients.

Results: The OVA(LPS)-OVA mice showed that the expression of ER stress markers and the protein levels of unfolded protein response-related markers in lung tissue were significantly increased after OVA challenge. Moreover, we found that ER stress markers in PBMCs and bronchoalveolar lavage fluid from human asthmatic patients were dramatically increased compared with those from healthy control subjects. In OVA(LPS)-OVA mice 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced the increases in ER stress, nuclear translocation of nuclear factor κB, inflammatory cytokine levels, dendritic cell infiltration, Toll-like receptor 4 expression, airway inflammation, and bronchial hyperresponsiveness, whereas it further enhanced the increase in IL-10 levels. Additionally, the established asthmatic features of OVA-OVA mice were substantially attenuated by 4-PBA administered after completion of OVA challenge.

Conclusion: These results indicate that ER stress might be implicated in the pathogenesis of bronchial asthma at least in part through modulation of nuclear factor κB activation.

Keywords: 4-PBA; 4-Phenylbutyric acid; ATF6; Activating transcription factor 6; BAL; Bronchial asthma; Bronchoalveolar lavage; CCAAT/enhancer-binding protein-homologous protein; CHOP; DC; DMSO; Dendritic cell; Dimethyl sulfoxide; ER; Endoplasmic reticulum; Enhanced pause; Eukaryotic initiation factor 2α; GAPDH; GRP78; Glucose-regulated protein 78; Glyceraldehyde-3-phosphate dehydrogenase; IL-10; KC; Keratinocyte-derived chemokine; MPO; Mice sensitized and challenged with OVA; Mice sensitized with OVA and LPS and challenged with OVA; Myeloperoxidase; NF-κB; Nuclear factor κB; OVA; OVA(LPS)-OVA mice; OVA-OVA mice; Ovalbumin; PAA; Penh; Phenylacetic acid; R(rs); Respiratory system resistance; SAL-SAL mice; SAL-SAL mice administered drug vehicle; SV mice; Saline-sensitized and saline-challenged mice; TLR; Toll-like receptor; Toll-like receptor 4; UPR; Unfolded protein response; X-box binding protein 1; XBP-1; eIF2α; endoplasmic reticulum stress; nuclear factor κB; phenylbutyric acid.