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Authors Wang Y, Zhou JS, Xu XC, Li ZY, Chen HP, Ying SM, Li W, Shen HH, Chen ZH
Received 1 September 2017
Accepted for publication 4 December 2017
Published 9 February 2018 Volume 2018:13 Pages 571—581
DOI https://doi.org/10.2147/COPD.S150633
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Charles Downs
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Chunxue Bai
Introduction: Bronchial epithelial cell death and airway inflammation induced by
cigarette smoke (CS) have been involved in the pathogenesis of COPD. GRP78,
belonging to heat shock protein 70 family, has been implicated in cell death
and inflammation, while little is known about its roles in COPD. Here, we
demonstrate that GRP78 regulates CS-induced necroptosis and injury in bronchial
epithelial cells.
Materials and
methods: GRP78 and necroptosis markers were
examined in human bronchial epithelial (HBE) cell line, primary mouse tracheal
epithelial cells, and mouse lungs. siRNA targeting GRP78 gene and necroptosis
inhibitor were used. Expression of inflammatory cytokines, mucin MUC5AC, and
related signaling pathways were detected.
Results: Exposure to CS significantly increased the expression of GRP78 and
necroptosis markers in HBE cell line, primary mouse tracheal epithelial cells,
and mouse lungs. Inhibition of GRP78 significantly suppressed CS extract
(CSE)-induced necroptosis. Furthermore, GRP78–necroptosis cooperatively
regulated CSE-induced inflammatory cytokines such as interleukin 6 (IL6), IL8,
and mucin MUC5AC in HBE cells, likely through the activation of nuclear factor
(NF-κB) and activator protein 1 (AP-1) pathways, respectively.
Conclusion: Taken together, our results demonstrate that GRP78 promotes
CSE-induced inflammatory response and mucus hyperproduction in airway
epithelial cells, likely through upregulation of necroptosis and subsequent
activation of NF-κB and AP-1 pathways. Thus, inhibition of GRP78 and/or
inhibition of necroptosis could be the effective therapeutic approaches for the
treatment of COPD.
Keywords: cigarette smoke, airway epithelium, glucose-regulated protein 78,
necroptosis, airway injury