Transcriptional profiling reveals gene expression changes associated with inflammation and cell proliferation following short-term inhalation exposure to copper oxide nanoparticles
Transcriptional profiling reveals gene expression changes associated with inflammation and cell proliferation following short-term inhalation exposure to copper oxide nanoparticles
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DOI：
10.1002/jat.3548
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发表时间：
2018-03-01
影响因子：
3.3
通讯作者：
Fadeel, Bengt
中科院分区：
文献类型：
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作者：
Costa, Pedro M.;Gosens, Ilse;Fadeel, Bengt
我们最近的研究表明，在连续五天短期吸入暴露后，大鼠对氧化铜纳米颗粒（CuO NP）会出现剂量依赖性促炎反应。在这里，使用相同的模型应用转录组学方法来评估暴露于清洁空气或 3.3 mg m(-3)（低剂量）和 13.2 mg m(-3)（高剂量）6 小时等效剂量的大鼠暴露后 1 天和 22 天恢复期后获得的肺组织中的整体基因表达。微阵列分析显示，与清洁空气对照组相比，高剂量组有约 1000 个差异表达基因，低剂量组有 200 个差异表达基因，恢复期后差异表达基因少于 20 个。通路分析表明细胞增殖/存活和炎症是暴露于 CuO NP 引发的主要过程。我们没有发现与氧化应激相关的途径有显着的扰动。注意到上皮细胞转化蛋白 2 (Ect2)（一种已知的癌基因）的上调，并且 ECT2 蛋白在暴露动物的肺部中上调。基于 Ki67 表达证明了肺泡上皮细胞的增殖。编码单核细胞趋化蛋白 1（或 CCL2）的基因也上调，这一点通过免疫组织化学得到证实。然而，没有观察到炎症相关基因的异常 DNA 甲基化。总之，我们发现大鼠吸入 CuO NPs 会导致癌蛋白 ECT2 和趋化因子 CCL2 以及其他促炎标记物上调，以及短期吸入暴露后支气管肺泡上皮细胞增殖。因此，已知与肿瘤过程和炎症相关的途径在该模型中受到影响。
Our recent studies revealed a dose-dependent proinflammatory response to copper oxide nanoparticles (CuO NPs) in rats following short-term inhalation exposure for five consecutive days. Here transcriptomics approaches were applied using the same model to assess global gene expression in lung tissues obtained 1 day post-exposure and after a recovery period of 22 days from rats exposed to clean air or 6 hour equivalent doses of 3.3 mg m(-3) (low dose) and 13.2 mg m(-3) (high dose). Microarray analyses yielded about 1000 differentially expressed genes in the high-dose group and 200 in low-dose compared to the clean air control group, and less than 20 after the recovery period. Pathway analysis indicated cell proliferation/survival and inflammation as the main processes triggered by exposure to CuO NPs. We did not find significant perturbations of pathways related to oxidative stress. Upregulation of epithelial cell transforming protein 2 (Ect2), a known oncogene, was noted and ECT2 protein was upregulated in the lungs of exposed animals. Proliferation of alveolar epithelial cells was demonstrated based on Ki67 expression. The gene encoding monocyte chemoattractant protein 1 (or CCL2) was also upregulated and this was confirmed by immunohistochemistry. However, no aberrant DNA methylation of inflammation-associated genes was observed. In conclusion, we have found that inhalation of CuO NPs in rats causes upregulation of the oncoprotein ECT2 and the chemokine CCL2 and other proinflammatory markers as well as proliferation in bronchoalveolar epithelium after a short-term inhalation exposure. Thus, pathways known to be associated with neoplastic processes and inflammation were affected in this model.