Peterson M W, Walter M E, Gross T J
Department of Medicine, University of Iowa, Iowa City 52242.
Am J Physiol. 1993 Sep;265(3 Pt 1):L308-17. doi: 10.1152/ajplung.1993.265.3.L308.
Asbestos causes the fibrotic lung disease asbestosis, but the biologic basis for this is unknown. Lung epithelial dysfunction including increased permeability is hypothesized to contribute to lung scarring in other forms of pulmonary fibrosis. Lung epithelial permeability is increased in both animals and humans exposed to asbestos. It is not known whether the increased epithelial permeability results from direct effects of asbestos or occurs as a result of the inflammatory reaction to asbestos fibers. To address this question we used a cultured human lung epithelial model, and we measured the direct effect of asbestos on lung epithelial barrier integrity as measured by mannitol permeability. We exposed the monolayer to chryogenically ground, respirable-sized chrysotile asbestos particles. This chrysotile asbestos caused a dose- and time-dependent increase in mannitol permeability across the epithelial monolayer. Increased mannitol permeability occurred both in the presence and in the absence of serum, was not due to cytotoxicity as measured by lactate dehydrogenase release, and was not associated with altered actin cytoskeleton at the light microscopic level. Permeability to 70 kDa neutral dextran also increased after asbestos exposure; however, the absolute permeability to dextran was less than mannitol permeability. Neither latex beads nor tantalum caused any change in permeability, suggesting that our findings are not explained by nonspecific effects of particles. Increased permeability did not reverse in the continued presence of asbestos and persisted even after removing the asbestos. Finally, surface-bound iron did not appear to be necessary for this effect because neither chelating iron with deferoxamine nor iron-loading the asbestos altered the effect on mannitol permeability. These results show that asbestos has direct effects on lung epithelial permeability. Together with the recent observation that asbestos directly increases epithelial fibrinolytic activity, our results suggest a novel mechanism for asbestos-induced lung injury.
石棉会引发纤维化肺病——石棉沉着病，但其生物学基础尚不清楚。包括通透性增加在内的肺上皮功能障碍被认为是导致其他形式肺纤维化中肺瘢痕形成的原因。在接触石棉的动物和人类中，肺上皮通透性均会增加。目前尚不清楚上皮通透性增加是由石棉的直接作用导致的，还是对石棉纤维炎症反应的结果。为了解决这个问题，我们使用了一种培养的人肺上皮模型，并通过测量甘露醇通透性来测定石棉对肺上皮屏障完整性的直接影响。我们将单层细胞暴露于经低温研磨、可吸入大小的温石棉颗粒中。这种温石棉导致上皮单层甘露醇通透性呈剂量和时间依赖性增加。无论有无血清，甘露醇通透性都会增加，这并非由乳酸脱氢酶释放所测量的细胞毒性引起，且在光学显微镜水平上与肌动蛋白细胞骨架改变无关。接触石棉后，70 kDa中性葡聚糖的通透性也增加了；然而，葡聚糖的绝对通透性低于甘露醇通透性。乳胶珠和钽均未引起通透性变化，这表明我们的发现不能用颗粒的非特异性效应来解释。在持续存在石棉的情况下，通透性增加并未逆转，甚至在去除石棉后仍持续存在。最后，表面结合的铁似乎并非产生这种效应所必需，因为用去铁胺螯合铁或使石棉负载铁均未改变对甘露醇通透性的影响。这些结果表明，石棉对肺上皮通透性有直接影响。结合最近观察到的石棉直接增加上皮纤维蛋白溶解活性，我们的结果提示了一种石棉诱导肺损伤的新机制。
