Cigarette smoke extract enhances neutrophil elastase-induced IL-8 production via proteinase-activated receptor-2 upregulation in human bronchial epithelial cells.
Cigarette smoke extract enhances neutrophil elastase-induced IL-8 production via proteinase-activated receptor-2 upregulation in human bronchial epithelial cells.
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DOI：
10.1038/s12276-018-0114-1
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发表时间：
2018-07-06
影响因子：
12.8
通讯作者：
Yoo CG
中科院分区：
文献类型：
--
作者：
Lee KH;Lee J;Jeong J;Woo J;Lee CH;Yoo CG
虽然炎症、氧化应激和蛋白酶-抗蛋白酶失衡被认为是慢性阻塞性肺疾病（COPD）的致病三联体，但对它们如何相互作用知之甚少。本研究旨在探讨香烟烟雾提取物（CSE）对中性粒细胞弹性蛋白酶（NE）诱导的支气管上皮细胞炎症反应的影响及其分子机制。我们观察到NE激活细胞外信号调节激酶（ERK）并诱导IL-8的产生。使用MEK抑制剂（U 0126）阻断ERK活化抑制NE诱导的IL-8分泌，并且使用siRNA敲低蛋白酶激活受体2（PAR 2）抑制NE诱导的ERK活化和随后的IL-8释放，这表明NE诱导的IL-8产生依赖于PAR 2介导的ERK活化。有趣的是，预先暴露于CSE显著增强NE诱导的IL-8产生。由于PAR 2充当NE的受体，我们接下来研究了CSE对PAR 2表达的影响，作为在CSE暴露的细胞中由NE诱导的IL-8产生增加的分子机制。CSE可增加PAR 2 mRNA和表面膜蛋白的表达，NE则无此作用。抑制p38 MAPK可降低CSE诱导的PAR 2表达，而抑制ERK和Akt通路则无影响。因此，p38抑制显着废除CSE诱导的NE处理的细胞中IL-8的产生的增强。值得注意的是，我们观察到来自CSE处理的小鼠以及来自吸烟者和COPD患者的肺匀浆和肺上皮细胞中PAR 2水平增加。总之，这些结果表明，CSE上调正常人支气管上皮细胞中的PAR 2，从而增强对NE的炎症反应。一项关于香烟烟雾提取物（CSE）对肺衬里细胞影响的研究阐明了CSE与一种与引起慢性阻塞性肺疾病（COPD）有关的酶之间的相互作用。弹性蛋白酶由嗜中性粒细胞释放，并且已知会诱导炎症，这会导致COPD中的肺刺激。韩国首尔国立大学的Chul-Gyu Yoo和同事将培养的人类肺细胞暴露于CSE。这种暴露激活了特定的分子信号传导过程，通过该过程增强了弹性蛋白酶诱导的炎症。特别值得注意的是CSE处理的细胞中细胞表面受体蛋白水平的增加。这种蛋白质在吸烟者和COPD患者的肺中增加。该研究有助于了解吸烟在COPD发病机制中的作用。
Although inflammation, oxidative stress, and protease-antiprotease imbalance have been referred to as a pathogenic triad in chronic obstructive pulmonary disease (COPD), little is known about how they interact. The objectives of this study were to elucidate the effect of cigarette smoke extract (CSE) on the neutrophil elastase (NE)-induced inflammatory response and its molecular mechanism in bronchial epithelial cells. We observed that NE activated extracellular signal-regulated kinase (ERK) and induced IL-8 production. Blocking ERK activation using a MEK inhibitor (U0126) suppressed NE-induced IL-8 secretion and knockdown of proteinase-activated receptor 2 (PAR2) using siRNAs inhibited both NE-induced ERK activation and subsequent IL-8 release, suggesting that NE-induced IL-8 production is dependent on PAR2-mediated ERK activation. Interestingly, pre-exposure to CSE markedly enhanced NE-induced IL-8 production. As PAR2 acts as a receptor for NE, we next investigated the effect of CSE on PAR2 expression as a molecular mechanism for the increased IL-8 production induced by NE in CSE exposed cells. CSE, but not NE, increased the expression of PAR2 mRNA and surface membrane protein. Inhibition of p38 MAPK reduced PAR2 expression induced by CSE while inhibition of the ERK and Akt pathway had no effect. Consequently, p38 inhibition significantly abrogated CSE-induced enhancement of IL-8 production in NE-treated cells. Of note, we observed increased PAR2 levels in lung homogenates and lung epithelial cells from CSE-treated mice and from both smokers and patients with COPD. Taken together, these results suggest that CSE upregulates PAR2 in normal human bronchial epithelial cells, thereby enhancing the inflammatory response to NE. A study of the effect of cigarette smoke extract (CSE) on lung lining cells clarifies the interaction between CSE and an enzyme implicated in causing chronic obstructive pulmonary disease (COPD). The enzyme elastase is released by neutrophils and is known to induce inflammation, which causes lung irritation in COPD. Chul-Gyu Yoo and colleagues at Seoul National University in South Korea exposed cultured human lung cells to CSE. This exposure activated specific molecular signaling processes by which the elastase enzyme-induced inflammation was enhanced. Of particular note was an increase in the levels of a cell surface receptor protein in CSE-treated cells. This protein was increased in lungs of smokers and COPD patients. The research helps to understand the role of cigarette smoking in the pathogenesis of COPD.
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