Background

Chronic obstructive pulmonary disease (COPD) is a severe public health problem. Cigarette smoke (CS) is a risk factor for COPD and lung cancer. The underlying molecular mechanisms of CS-induced malignant transformation of bronchial epithelial cells remain unclear. In this study, we describe a lung-on-a-chip to explore the possible mechanistic link between cigarette smoke extract (CSE)-associated COPD and lung cancer.

Methods

An in vitro lung-on-a-chip model was used to simulate pulmonary epithelial cells and vascular endothelial cells with CSE. The levels of IL-6 and TNF-α were tested as indicators of inflammation using an enzyme-linked immune sorbent assay. Apical junction complex mRNA expression was detected with qRT-PCR as the index of epithelial-to-mesenchymal transition (EMT). The effects of CSE on the phosphorylation of signal transduction and transcriptional activator 3 (STAT3) were detected by Western blotting. Flow cytometry was performed to investigate the effects of this proto-oncogene on cell cycle distribution.

Results

Inflammation caused by CSE was achieved in a lung-on-a-chip model with a mimetic movement. CSE exposure induced the degradation of intercellular connections and triggered the EMT process. CSE exposure also activated the phosphorylation of proto-oncogene STAT3, while these effects were inhibited with HJC0152.

Conclusions

CSE exposure in the lung-on-a-chip model caused activation of STAT3 in epithelial cells and endothelial cells. HJC0152, an inhibitor of activated STAT3, could be a potential treatment for CS-associated COPD and lung cancer.

中文翻译：

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在单片肺模型中通过STAT3信号传导香烟烟雾诱导的恶性转化

背景

慢性阻塞性肺疾病（COPD）是一个严重的公共卫生问题。香烟烟雾（CS）是COPD和肺癌的危险因素。CS诱导的支气管上皮细胞恶性转化的潜在分子机制仍不清楚。在这项研究中，我们描述了一种片上肺，以探讨香烟烟雾提取物（CSE）相关的COPD与肺癌之间可能的机械联系。

方法

体外单芯片肺模型用于通过CSE模拟肺上皮细胞和血管内皮细胞。使用酶联免疫吸附测定法测试了IL-6和TNF-α的水平作为炎症指标。用qRT-PCR检测上皮结复合物mRNA表达，作为上皮-间质转化（EMT）的指标。通过蛋白质印迹法检测了CSE对信号转导和转录激活因子3（STAT3）磷酸化的影响。进行流式细胞术以研究该原癌基因对细胞周期分布的影响。

结果

由CSE引起的炎症是在具有模拟运动的单片肺模型中实现的。CSE暴露引起细胞间连接的降解并引发EMT过程。CSE暴露还激活了原癌基因STAT3的磷酸化，而HJC0152抑制了这些作用。

结论

芯片上肺模型中的CSE暴露引起上皮细胞和内皮细胞中STAT3的激活。HJC0152，一种活化的STAT3抑制剂，可能是与CS相关的COPD和肺癌的潜在治疗方法。