Health Effects Laboratory Division, National Institute for Occupational Safety and Health (NIOSH), Morgantown, West Virginia 26505.
Toxicol Sci. 2020 Dec 1;178(2):375-390. doi: 10.1093/toxsci/kfaa146.
Smoking may modify the lung response to silica exposure including cancer and silicosis. Nevertheless, the precise role of exposure to tobacco smoke (TS) on the lung response to crystalline silica (CS) exposure and the underlying mechanisms need further clarification. The objectives of the present study were to determine the role of TS on lung response to CS exposure and the underlying mechanism(s). Male Fischer 344 rats were exposed by inhalation to air, CS (15 mg/m3, 6 h/day, 5 days), TS (80 mg/m3, 3 h/day, twice weekly, 6 months), or CS (15 mg/m3, 6 h/day, 5 days) followed by TS (80 mg/m3, 3 h/day, twice weekly, 6 months). The rats were euthanized 6 months and 3 weeks following initiation of the first exposure and the lung response was assessed. Silica exposure resulted in significant lung toxicity as evidenced by lung histological changes, enhanced neutrophil infiltration, increased lactate dehydrogenase levels, enhanced oxidant production, and increased cytokine levels. The TS exposure alone had only a minimal effect on these toxicity parameters. However, the combined exposure to TS and CS exacerbated the lung response, compared with TS or CS exposure alone. Global gene expression changes in the lungs correlated with the lung toxicity severity. Bioinformatic analysis of the gene expression data demonstrated significant enrichment in functions, pathways, and networks relevant to the response to CS exposure which correlated with the lung toxicity detected. Collectively our data demonstrated an exacerbation of CS-induced lung toxicity by TS exposure and the molecular mechanisms underlying the exacerbated toxicity.
吸烟可能会改变肺部对二氧化硅暴露的反应，包括癌症和矽肺。然而，确切的烟草烟雾（TS）暴露对结晶二氧化硅（CS）暴露的肺部反应的作用以及潜在机制仍需进一步阐明。本研究的目的是确定 TS 对 CS 暴露后肺部反应的作用及其潜在机制。雄性 Fischer 344 大鼠通过吸入空气、CS（15mg/m3，6h/d，5d）、TS（80mg/m3，3h/d，每周两次，6 个月）或 CS（15mg/m3，6h/d，5d）进行暴露，然后进行 TS（80mg/m3，3h/d，每周两次，6 个月）暴露。大鼠在第一次暴露后 6 个月和 3 周时被安乐死，评估肺部反应。二氧化硅暴露导致明显的肺毒性，表现为肺组织学改变、中性粒细胞浸润增加、乳酸脱氢酶水平升高、氧化应激产物增加和细胞因子水平升高。TS 单独暴露对这些毒性参数只有很小的影响。然而，TS 和 CS 的联合暴露与 TS 或 CS 单独暴露相比，加剧了肺部反应。肺组织中的全基因表达变化与肺毒性严重程度相关。基因表达数据的生物信息学分析表明，与 CS 暴露反应相关的功能、途径和网络显著富集，并与检测到的肺毒性相关。总的来说，我们的数据表明，TS 暴露加剧了 CS 诱导的肺毒性，以及加剧毒性的潜在分子机制。
