Endoplasmic reticulum chaperone GRP78 mediates cigarette smoke-induced necroptosis and injury in bronchial epithelium.
Endoplasmic reticulum chaperone GRP78 mediates cigarette smoke-induced necroptosis and injury in bronchial epithelium.
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内质网伴侣GRP78介导香烟烟雾引起的坏死性凋亡和支气管上皮损伤
DOI：
10.2147/copd.s150633
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发表时间：
2018
影响因子：
2.8
通讯作者：
Chen ZH
中科院分区：
文献类型：
--
作者：
Wang Y;Zhou JS;Xu XC;Li ZY;Chen HP;Ying SM;Li W;Shen HH;Chen ZH
吸烟引起的支气管上皮细胞死亡和气道炎症参与了COPD的发病机制。GRP 78属于热休克蛋白70家族，与细胞死亡和炎症有关，但其在COPD中的作用尚不清楚。在这里，我们证明GRP 78调节CS诱导的支气管上皮细胞坏死性凋亡和损伤。材料与方法采用人支气管上皮细胞系、小鼠原代气管上皮细胞和小鼠肺组织，检测GRP 78和坏死性凋亡标志物。使用靶向GRP 78基因的siRNA和坏死性凋亡抑制剂。检测炎性细胞因子、粘蛋白MUC 5AC的表达及相关信号通路。结果CS可显著增加HBE细胞系、原代小鼠气管上皮细胞和小鼠肺组织中GRP 78和坏死性凋亡标志物的表达。GRP 78的抑制显著抑制CS提取物（CSE）诱导的坏死性凋亡。此外，GRP 78-坏死性凋亡协同调节CSE诱导的炎症细胞因子，如HBE细胞中的白细胞介素6（IL 6）、IL 8和粘蛋白MUC 5AC，可能分别通过激活核因子（NF-κB）和激活蛋白1（AP-1）途径。结论GRP 78可促进CSE诱导的气道上皮细胞炎症反应和粘液分泌，其机制可能与其上调坏死性凋亡及随后激活NF-κB和AP-1通路有关。因此，抑制GRP 78和/或抑制坏死性凋亡可能是治疗COPD的有效治疗方法。
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.