Balharry Dominique, Sexton Keith, BéruBé Kelly A
Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, South Glamorgan, CF10 3US, UK.
Toxicology. 2008 Feb 3;244(1):66-76. doi: 10.1016/j.tox.2007.11.001. Epub 2007 Nov 9.
One of the first lines of defence to inhaled toxins is the barrier formed by the tracheobronchial epithelium, making this the ideal region for studying the toxicity of inhaled substances. This study utilises a highly differentiated, three-dimensional, in vitro model of human upper respiratory tract epithelium (EpiAirway-100) to measure the acute toxicological responses to well-characterised tobacco smoke components. To determine the suitability of this model for screening inhaled toxicants, the EpiAirway tissue model (ETM) was treated apically with tobacco smoke components (nicotine, formaldehyde, cadmium, urethane) which are known to induce a variety of toxic effects (e.g. cytotoxic, thrombogenic, carcinogenic). A range of concentrations were used to model different mechanisms and severity of toxicity which were then compared to known in vivo responses. Similar trends in stress response occurred, with distinct alterations to the tissue in response to all four toxins. At high concentrations, cell viability decreased and tight junctions were degraded, but at sub-toxic concentrations epithelial resistance (indicating tissue integrity) increased 20-60% from control. This peak in resistance coincided with an increase in secreted protein levels, elevated cytokine release and goblet cell hyperplasia and hypertrophy. In conclusion, acute exposure to tobacco smoke components induces measurable toxic responses within human respiratory epithelium. Sub-toxic concentrations appear to illicit a protective response by increasing mucus secretion and mediating immune responses via cytokine release. These responses are comparable to human in vivo responses, indicating potential for the ETM as a tool for screening the toxicity of inhaled compounds.
吸入毒素的第一道防线之一是气管支气管上皮形成的屏障，这使得该区域成为研究吸入物质毒性的理想区域。本研究利用一种高度分化的、三维的人上呼吸道上皮体外模型（EpiAirway-100）来测量对特征明确的烟草烟雾成分的急性毒理学反应。为了确定该模型用于筛选吸入毒物的适用性，用已知会诱导多种毒性作用（如细胞毒性、血栓形成、致癌性）的烟草烟雾成分（尼古丁、甲醛、镉、聚氨酯）对EpiAirway组织模型（ETM）进行顶端处理。使用一系列浓度来模拟不同的毒性机制和严重程度，然后与已知的体内反应进行比较。应激反应出现了类似的趋势，对所有四种毒素的反应导致组织有明显改变。在高浓度下，细胞活力下降，紧密连接降解，但在亚毒性浓度下，上皮电阻（表明组织完整性）比对照增加了20 - 60%。这种电阻峰值与分泌蛋白水平增加、细胞因子释放升高以及杯状细胞增生和肥大同时出现。总之，急性暴露于烟草烟雾成分会在人呼吸道上皮内诱导可测量的毒性反应。亚毒性浓度似乎通过增加黏液分泌和通过细胞因子释放介导免疫反应引发一种保护反应。这些反应与人体体内反应相当，表明ETM作为筛选吸入化合物毒性工具的潜力。
