Kamp D W, Israbian V A, Yeldandi A V, Panos R J, Graceffa P, Weitzman S A
Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Toxicol Pathol. 1995 Nov-Dec;23(6):689-95. doi: 10.1177/019262339502300606.
Reactive oxygen species, especially iron-catalyzed hydroxyl radicals (.OH) are implicated in the pathogenesis of asbestos-induced pulmonary toxicity. We previously demonstrated that phytic acid, an iron chelator, reduces amosite asbestos-induced .OH generation, DNA strand break formation, and injury to cultured pulmonary epithelial cells (268[1995, Am. J. Physiol.(Lung Cell. Mol. Physiol.) 12:L471-480]). To determine whether phytic acid diminishes pulmonary inflammation and fibrosis in rats after a single intratracheal (it) instillation of amosite asbestos, Sprague-Dawley rats were given either saline (1 ml), amosite asbestos (5 mg; 1 ml saline), or amosite treated with phytic acid (500 microM) for 24 hr and then instilled. At various times after asbestos exposure, the rats were euthanized and the lungs were lavaged and examined histologically. A fibrosis score was determined from trichrome-stained specimens. As compared to controls, asbestos elicited a significant pulmonary inflammatory response, as evidence by an increase (approximately 2-fold) in bronchoalveolar lavage (BAL) cell counts at 1 wk and the percentage of BAL neutrophils (PMNs) and giant cells at 2 wk (0.1 vs 6.5% and 1.3 vs 6.1%, respectively; p < 0.05). Asbestos significantly increased the fibrosis score at 2 wk (0 +/- 0 vs 5 +/- 1; p < 0.05). The inflammatory and fibrotic changes were, as expected, observed in the respiratory bronchioles and terminal alveolar duct bifurcations. The increased percentage of BAl PMNs and giant cells persisted at 4 wk, as did the fibrotic changes. Compared to asbestos alone, phytic acid-treated asbestos elicited significantly less BAL PMNs (6.5 vs 1.0%; p < 0.05) and giant cells (6.1 vs 0.2%; p < 0.05) and caused significantly less fibrosis (5 vs 0.8; p < 0.05) 2 wk after exposure. We conclude that asbestos causes pulmonary inflammation and fibrosis in rats after it instillation and that phytic acid reduces these effects. These data support the role of iron-catalyzed free radicals in causing pulmonary toxicity from asbestos in vivo.
活性氧物质，尤其是铁催化产生的羟基自由基（·OH）与石棉诱导的肺毒性发病机制有关。我们之前证明，铁螯合剂植酸可减少铁石棉诱导的·OH生成、DNA链断裂形成以及对培养的肺上皮细胞的损伤（268[1995年，《美国生理学杂志》（肺细胞与分子生理学）12:L471 - 480]）。为了确定植酸是否能减轻大鼠单次气管内（it）注入铁石棉后的肺部炎症和纤维化，给Sprague - Dawley大鼠分别注入生理盐水（1 ml）、铁石棉（5 mg；1 ml生理盐水）或用植酸（500 microM）处理24小时后的铁石棉，然后进行注入。在石棉暴露后的不同时间，对大鼠实施安乐死，冲洗肺部并进行组织学检查。根据三色染色标本确定纤维化评分。与对照组相比，石棉引发了显著的肺部炎症反应，证据是1周时支气管肺泡灌洗（BAL）细胞计数增加（约2倍），以及2周时BAL中性粒细胞（PMN）和巨细胞百分比增加（分别为0.1%对6.5%和1.3%对6.1%；p < 0.05）。石棉在2周时显著增加了纤维化评分（0 ± 0对5 ± 1；p < 0.05）。如预期的那样，在呼吸细支气管和终末肺泡管分支处观察到了炎症和纤维化变化。BAL PMN和巨细胞百分比增加在4周时持续存在，纤维化变化也是如此。与单独使用石棉相比，植酸处理的石棉在暴露2周后引发的BAL PMN显著减少（6.5%对1.0%；p < 0.05）和巨细胞显著减少（6.1%对0.2%；p < 0.05），并且纤维化程度显著减轻（5对0.8；p < 0.05）。我们得出结论，石棉在大鼠气管内注入后会导致肺部炎症和纤维化，而植酸可减轻这些影响。这些数据支持铁催化自由基在体内石棉引起肺毒性中的作用。
