Haegens Astrid, van der Vliet Albert, Butnor Kelly J, Heintz Nicholas, Taatjes Douglas, Hemenway David, Vacek Pamela, Freeman Bruce A, Hazen Stanley L, Brennan Marie Luise, Mossman Brooke T
Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont 05404, USA.
Cancer Res. 2005 Nov 1;65(21):9670-7. doi: 10.1158/0008-5472.CAN-05-1751.
Asbestos fibers are carcinogens causing oxidative stress and inflammation, but the sources and ramifications of oxidant production by asbestos are poorly understood. Here, we show that inhaled chrysotile asbestos fibers cause increased myeloperoxidase activity in bronchoalveolar lavage fluids (BALF) and myeloperoxidase immunoreactivity in epithelial cells lining distal bronchioles and alveolar ducts, sites of initial lung deposition of asbestos fibers. In comparison with sham mice, asbestos-exposed myeloperoxidase-null (MPO-/-) and normal (MPO+/+) mice exhibited comparable increases in polymorphonuclear leukocytes, predominately neutrophils, in BALF after 9 days of asbestos inhalation. Differential cell counts on BALF revealed decreased proportions of macrophages and increased lymphocytes in all mice exposed to asbestos, but numbers were decreased overall in asbestos-exposed myeloperoxidase-null versus normal mice. Asbestos-associated lung inflammation in myeloperoxidase-null mice was reduced (P < or = 0.05) in comparison with normal asbestos-exposed mice at 9 days. Decreased lung inflammation in asbestos-exposed myeloperoxidase-null mice at 9 days was accompanied by increases (P < or = 0.05) in Ki-67- and cyclin D1-positive immunoreactive cells, markers of cell cycle reentry, in the distal bronchiolar epithelium. Asbestos-induced epithelial cell proliferation in myeloperoxidase-null mice at 30 days was comparable to that found at 9 days. In contrast, inflammation and epithelial cell proliferation in asbestos-exposed normal mice increased over time. These results support the hypothesis that myeloperoxidase status modulates early asbestos-induced oxidative stress, epithelial cell proliferation, and inflammation.
石棉纤维是致癌物，可引起氧化应激和炎症，但石棉产生氧化剂的来源和后果却知之甚少。在此，我们表明，吸入的温石棉纤维会导致支气管肺泡灌洗液（BALF）中的髓过氧化物酶活性增加，以及在细支气管远端和肺泡管内衬的上皮细胞中出现髓过氧化物酶免疫反应性，这些部位是石棉纤维在肺部最初沉积的地方。与假手术小鼠相比，吸入石棉9天后，暴露于石棉的髓过氧化物酶缺陷（MPO-/-）和正常（MPO+/+）小鼠的支气管肺泡灌洗液中多形核白细胞（主要是中性粒细胞）数量均有类似增加。对支气管肺泡灌洗液进行的细胞分类计数显示，所有暴露于石棉的小鼠中巨噬细胞比例下降，淋巴细胞增加，但与正常小鼠相比，暴露于石棉的髓过氧化物酶缺陷小鼠的细胞总数总体减少。在第9天时，与正常暴露于石棉的小鼠相比，髓过氧化物酶缺陷小鼠中与石棉相关的肺部炎症有所减轻（P≤0.05）。暴露于石棉的髓过氧化物酶缺陷小鼠在第9天时肺部炎症减轻，同时细支气管远端上皮细胞中细胞周期再进入的标志物Ki-67和细胞周期蛋白D1阳性免疫反应细胞增加（P≤0.05）。暴露于石棉的髓过氧化物酶缺陷小鼠在30天时石棉诱导的上皮细胞增殖与第9天时相当。相比之下，暴露于石棉的正常小鼠的炎症和上皮细胞增殖随时间增加。这些结果支持了这样一种假说，即髓过氧化物酶状态调节早期石棉诱导的氧化应激、上皮细胞增殖和炎症。
