Benzalkonium chloride and cetylpyridinium chloride induce apoptosis in human lung epithelial cells and alter surface activity of pulmonary surfactant monolayers
Benzalkonium chloride and cetylpyridinium chloride induce apoptosis in human lung epithelial cells and alter surface activity of pulmonary surfactant monolayers
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DOI：
10.1016/j.cbi.2020.108962
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发表时间：
2020-02-01
影响因子：
5.1
通讯作者：
Aoki, Yasuhiro
中科院分区：
文献类型：
--
作者：
Kanno, Sanae;Hirano, Seishiro;Aoki, Yasuhiro
季铵类化合物（如苯扎氯铵（BAC）和氯化十六烷基吡啶（CPC））是一类阳离子表面活性剂，尽管具有潜在的肺毒性，但仍广泛用于个人卫生和医疗保健。为了研究沉积在肺泡区的BAC和CPC气溶胶是否会改变肺功能，我们采用两步体外模型研究了对肺表面活性物质的影响；A549肺泡上皮细胞的细胞毒性以及使用Surfacten (R)和1,2-双棕榈酰- cn -甘油-3-磷酸胆碱（DPPC）的肺表面活性剂单层表面活性的变化。细胞活力随BAC和CPC剂量依赖性降低。不同烷基链长度的BAC同系物的细胞毒性比较表明，烷基链最长的C-16-BAC比C-12-和C-14-BAC的细胞毒性更大。在BAC和cpc暴露的细胞中，caspase-3 /7活性和caspase-3和PARP的裂解形式均升高。caspase-3-抑制剂可消除升高的caspase-3/7活性及其裂解活性形式。此外，我们通过Langmuir-Wilhelmy方法和原子力显微镜（AFM）图像检查了含有BAC， CPC或氯化吡啶（PC，作为对照）的亚相上脂质单层的表面压力/谷面积（pi-A）等温线的特征。pi-A等温线显示，在没有压缩的情况下，添加BAC或CPC会产生剂量依赖性的表面压力增加，表明BAC和CPC在较低压力下将等温线扩展到更大的区域。崩落压力随CPC浓度的增加而减小。地形图像表明，与对照组相比，BAC和CPC导致更小的凝聚脂质结构域。相反，不含烃尾的PC组没有细胞毒性，也没有改变等温线和AFM图像。这些结果表明，BAC和CPC通过caspase-3依赖性凋亡途径导致A549细胞死亡，并改变肺泡表面活性剂活性。这些影响可归因于BAC和CPC的长烷基链。
Quaternary ammonium compounds (e.g., benzalkonium chloride (BAC) and cetylpyridinium chloride (CPC)) constitute a group of cationic surfactants are widely used for personal hygiene and medical care despite the potential pulmonary toxicity. To examine whether BAC and CPC aerosols deposited in the alveolar region alter pulmonary function, we studied the effects on pulmonary surfactant using two-step in vitro models; cytotoxicity using A549 alveolar epithelial cell and changes in surface activity of the pulmonary surfactant monolayer using both Surfacten (R) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Cell viability was decreased with BAC and CPC dose-dependently. A comparison of cytotoxicity among BAC homologues with different length of alkyl chain showed that C-16-BAC, which has the longest alkyl chain, was more cytotoxic than C-12- or C-14-BAC. Caspase-3/7 activity and cleaved form of caspase-3 and PARP were increased in BAC- and CPC-exposed cells. The elevated caspase-3/7 activity and their cleaved active forms were abolished by caspase-3-inhibitor. Furthermore, we examined the features of the surface pressure/trough area (pi-A) isotherm by the Langmuir-Wilhelmy method and atomic force microscopy (AFM) images of lipid monolayers on a subphase containing BAC, CPC, or pyridinium chloride (PC, as a control). The pi-A isotherms showed that addition of BAC or CPC yielded dose-dependent increases in surface pressure without compression, indicating that BAC and CPC expand the isotherm to larger areas at lower pressure. The collapse pressure diminished with increasing concentration of CPC. Topographic images indicated that BAC and CPC resulted in smaller condensed lipid domains compared to the control. Conversely, PC without hydrocarbon tail group, showed no cytotoxicity and did not change the isotherms and AFM images. These results indicate that BAC and CPC cause cell death via caspase-3-dependent apoptotic pathway in A549 cells and alter the alveolar surfactant activity. These effects can be attributed to the long alkyl chain of BAC and CPC.