Mechanisms of allergy and clinical immunology
Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor κB activation

https://doi.org/10.1016/j.jaci.2013.08.041Get rights and content

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 (OVALPS-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 OVALPS-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 OVALPS-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.

Section snippets

Methods

The details of the methods used in this study can be found in the Methods section in this article's Online Repository at www.jacionline.org.

ER stress markers are increased in our murine model of asthma and the patients with asthma

Expression levels of GRP78 and CHOP in lung tissue were determined by using RT-PCR and real-time RT-PCR to evaluate the excess of ER stress in mice sensitized with OVA and LPS and challenged with OVA (OVALPS-OVA mice). The results revealed that mRNA levels of GRP78 and CHOP in lung tissue of OVALPS-OVA mice were gradually increased up to 24 hours after the last challenge with OVA, and the increased levels of mRNAs were then maintained up to 72 hours (Fig 1, A-D). Western blot analyses revealed

Discussion

To the best of our knowledge, the current study has dealt with the implication of ER stress in the pathogenesis of bronchial asthma, specifically of neutrophilic asthma, for the first time. Our data using the pharmacologic intervention with 4-PBA, an ER stress regulator, have been concentrated to support the hypothesis that ER stress plays an important role in inducing and maintaining bronchial asthma and therefore the modulation of ER stress can be a valuable pharmacologic target for

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    • Cited by (0)

    Supported by the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (grants A084144, A121931 [to Y.C.L.], and A111992 [to S.R.K.]) and the fund of the Biomedical Research Institute, Chonbuk National University Hospital.

    Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

    ∗

    These authors contributed equally to this work.

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    Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.