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首页> 外文期刊>International Journal of Environmental Research and Public Health >Microtubules as a Critical Target for Arsenic Toxicity in Lung Cells in Vitro and in Vivo
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Microtubules as a Critical Target for Arsenic Toxicity in Lung Cells in Vitro and in Vivo

机译：微管作为体内和体外肺细胞砷毒性的重要靶标

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To understand mechanisms for arsenic toxicity in the lung, we examined effects of sodium m-arsenite (As3+) on microtubule (MT) assembly in vitro (0–40 μM), in cultured rat lung fibroblasts (RFL6, 0–20 μM for 24 h) and in the rat animal model (intratracheal instillation of 2.02 mg As/kg body weight, once a week for 5 weeks). As3+ induced a dose-dependent disassembly of cellular MTs and enhancement of the free tubulin pool, initiating an autoregulation of tubulin synthesis manifest as inhibition of steady-state mRNA levels of βI-tubulin in dosed lung cells and tissues. Spindle MT injuries by As3+ were concomitant with chromosomal disorientations. As3+ reduced the binding to tubulin of [3H]N-ethylmaleimide (NEM), an -SH group reagent, resulting in inhibition of MT polymerization in vitro with bovine brain tubulins which was abolished by addition of dithiothreitol (DTT) suggesting As3+ action upon tubulin through -SH groups. In response to As3+, cells elevated cellular thiols such as metallothionein. Taxol, a tubulin polymerization agent, antagonized both As3+ and NEM induced MT depolymerization. MT–associated proteins (MAPs) essential for the MT stability were markedly suppressed in As3+-treated cells. Thus, tubulin sulfhydryls and MAPs are major molecular targets for As3+ damage to the lung triggering MT disassembly cascades.
机译：为了解肺中砷中毒的机制，我们在培养的大鼠肺成纤维细胞（RFL6，0–20μM，24小时）中检测了亚砷酸钠（As3 +）对体外微管（MT）装配的影响（0–40μM） h）和大鼠动物模型（气管内滴注2.02 mg As / kg体重，每周一次，持续5周）。 As3 +诱导了细胞MT的剂量依赖性分解和游离微管蛋白池的增强，启动了微管蛋白合成的自动调节，表现为抑制了剂量肺细胞和组织中βI-微管蛋白的稳态mRNA水平。 As3 +引起的主轴MT损伤伴有染色体定向障碍。 As3 +减少了-SH组试剂[3H] N-乙基马来酰亚胺（NEM）与微管蛋白的结合，导致牛脑微管蛋白在体外对MT聚合的抑制作用被二硫苏糖醇（DTT）消除，表明As3 +对微管蛋白有作用。通过-SH组。响应As3 +，细胞升高了细胞硫醇，例如金属硫蛋白。紫杉醇，微管蛋白聚合剂，拮抗As3 +和NEM诱导的MT解聚。 MT稳定性必需的MT相关蛋白（MAP）在经As3 +处理的细胞中被显着抑制。因此，微管蛋白巯基和MAPs是As3 +损伤肺触发MT分解级联反应的主要分子靶标。

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