Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
Toxicology. 2013 Dec 6;314(1):112-24. doi: 10.1016/j.tox.2013.09.013. Epub 2013 Oct 1.
Cigarette smoking is the primary etiology of chronic obstructive pulmonary disease (COPD) and a risk factor for both lung and cardiovascular (CV) diseases, which are rarely investigated concomitantly. Although smoking cessation shows clear CV risk benefit, lung-related disease risk remains higher in former smokers than in never smokers. We sought to determine the differential molecular responses of murine respiratory tissues to better understand the toxicity pathways involved in smoking-related disease risk and those related to the benefits of smoking cessation. ApoE(-/-) mice were exposed to mainstream cigarette smoke (CS) or a smoking cessation-mimicking protocol for up to 6 months and transcriptomics analysis of nasal epithelium and lung parenchyma performed. We supported our gene expression profiling approach with standard lung histopathology and bronchoalveolar lavage fluid (BALF) analysis. Many BALF analytes involved in functions ranging from inflammation to cell proliferation and tissue remodeling were found elevated in BALF. Gene expression levels of these molecules were also increased in lung tissue, suggesting that the inflammatory response was the result of local tissue activation and the contribution of recruited inflammatory cells. Gene set enrichment analysis (GSEA) of expression data from murine lungs and nasal epithelium showed distinct activation patterns of inflammation, complement, and xenobiotic metabolism pathways during CS exposure that were deactivated upon smoking cessation. Pathways involved in cell proliferation and tissue remodeling were activated by CS and progressively deactivated upon smoke exposure cessation. Differential CS-mediated responses of pulmonary and nasal tissues reflect common mechanisms but also the varying degrees of epithelial functional specialization and exposure along the respiratory tract.
吸烟是慢性阻塞性肺疾病（COPD）的主要病因，也是肺部和心血管（CV）疾病的危险因素，而这两种疾病很少同时进行调查。尽管戒烟对心血管风险有明显的益处，但与从不吸烟者相比，前吸烟者肺部相关疾病的风险仍然更高。我们试图确定鼠类呼吸组织对不同分子的反应，以更好地了解与吸烟相关疾病风险相关的毒性途径以及与戒烟益处相关的毒性途径。apoE（-/-）小鼠暴露于主流香烟烟雾（CS）或戒烟模拟方案中长达 6 个月，并对鼻上皮和肺实质进行了转录组学分析。我们用标准的肺组织病理学和支气管肺泡灌洗液（BALF）分析来支持我们的基因表达谱分析方法。在 BALF 中发现许多涉及从炎症到细胞增殖和组织重塑等功能的 BALF 分析物升高。这些分子的基因表达水平在肺组织中也增加，这表明炎症反应是局部组织激活和募集的炎症细胞的贡献的结果。来自鼠肺和鼻上皮的表达数据的基因集富集分析（GSEA）显示，CS 暴露期间炎症、补体和异生物质代谢途径的激活模式明显不同，戒烟后这些途径被失活。CS 诱导的细胞增殖和组织重塑途径被激活，并随着烟雾暴露的停止而逐渐失活。肺部和鼻腔组织对 CS 的不同反应反映了共同的机制，但也反映了沿呼吸道上皮功能专业化和暴露程度的不同。
