Asbestos-induced alveolar epithelial cell apoptosis: Role of mitochondrial dysfunction caused by iron-derived free radicals
Asbestos-induced alveolar epithelial cell apoptosis: Role of mitochondrial dysfunction caused by iron-derived free radicals
复制标题
DOI：
10.1023/a:1015949118495
复制
发表时间：
2002-05-01
影响因子：
4.3
通讯作者：
Chandel, N
中科院分区：
文献类型：
--
作者：
Kamp, DW;Panduri, V;Chandel, N
石棉引起石棉沉着病和恶性肿瘤的机制尚不完全清楚。铁源性活性氧（ROS）对肺泡上皮细胞（AEC）的损伤是其重要机制之一。我们以前表明，铁催化的活性氧部分介导石棉诱导的AEC DNA损伤和凋亡。线粒体在暴露于引起DNA损伤的物质后调节细胞凋亡中具有关键作用，但其在调节石棉诱导的细胞凋亡中的作用尚不清楚。为了确定石棉是否会导致AEC线粒体功能障碍，我们将A549细胞暴露于石棉，并使用涉及四甲基罗丹明乙酯（TMRE）和mitotracker绿色的荧光技术评估线粒体膜电位变化（Δ Psi（m））。我们表明，铁石棉，但不是一种惰性颗粒，二氧化钛，减少Δ sigma（m）后，4小时的曝光期。此外，如通过核形态学以及DNA核小体形成所评估的，4小时后的Δ σ（m）与24小时时注意到的细胞凋亡水平成反比。铁螯合剂植酸阻断石棉诱导的A549细胞Deltasigma（m）减少并减弱细胞凋亡，这一发现表明铁源性ROS的作用。最后，Bcl-xl（一种定位于线粒体的抗凋亡蛋白）的过表达阻止了石棉诱导的A549细胞Deltasigma（m）在4小时后的减少，并减少了凋亡。我们的结论是，石棉改变AEC线粒体功能的一部分，通过产生铁源性活性氧，这反过来又可以导致细胞凋亡。这表明线粒体死亡途径在调节石棉的肺毒性方面很重要。
Asbestos causes asbestosis and malignancies by mechanisms that are not fully understood. Alveolar epithelial cell (AEC) injury by iron-derived reactive oxygen species (ROS) is one important mechanism implicated. We previously showed that iron-catalyzed ROS in part mediate asbestos-induced AEC DNA damage and apoptosis. Mitochondria have a critical role in regulating apoptosis after exposure to agents causing DNA damage but their role in regulating asbestos-induced apoptosis is unknown. To determine whether asbestos causes AEC mitochondrial dysfunction, we exposed A549 cells to amosite asbestos and assessed mitochondrial membrane potential changes (DeltaPsi(m)) using a fluorometric technique involving tetremethylrhodamine ethyl ester (TMRE) and mitotracker green. We show that amosite asbestos, but not an inert particulate, titanium dioxide, reduces Deltasigma(m) after a 4 h exposure period. Further, the Deltasigma(m) after 4 h was inversely proportional to the levels of apoptosis noted at 24 h as assessed by nuclear morphology as well as by DNA nucleosome formation. A role for iron-derived ROS was suggested by the finding that phytic acid, an iron chelator, blocked asbestos-induced reductions in A549 cell Deltasigma(m) and attenuated apoptosis. Finally, overexpression of Bcl-xl, an anti-apoptotic protein that localizes to the mitochondria, prevented asbestos-induced decreases in A549 cell Deltasigma(m) after 4 h and diminished apoptosis. We conclude that asbestos alters AEC mitochondrial function in part by generating iron-derived ROS, which in turn can result in apoptosis. This suggests that the mitochondrial death pathway is important in regulating pulmonary toxicity from asbestos.