Laboratory of Nanotoxicology Project, Nagoya City University, Nagoya, Japan.
Cancer Sci. 2012 Dec;103(12):2045-50. doi: 10.1111/cas.12005. Epub 2012 Oct 10.
Multi-walled carbon nanotubes have a fibrous structure similar to asbestos and induce mesothelioma when injected into the peritoneal cavity. In the present study, we investigated whether carbon nanotubes administered into the lung through the trachea induce mesothelial lesions. Male F344 rats were treated with 0.5 mL of 500 μg/mL suspensions of multi-walled carbon nanotubes or crocidolite five times over a 9-day period by intrapulmonary spraying. Pleural cavity lavage fluid, lung and chest wall were then collected. Multi-walled carbon nanotubes and crocidolite were found mainly in alveolar macrophages and mediastinal lymph nodes. Importantly, the fibers were also found in the cell pellets of the pleural cavity lavage, mostly in macrophages. Both multi-walled carbon nanotube and crocidolite treatment induced hyperplastic proliferative lesions of the visceral mesothelium, with their proliferating cell nuclear antigen indices approximately 10-fold that of the vehicle control. The hyperplastic lesions were associated with inflammatory cell infiltration and inflammation-induced fibrotic lesions of the pleural tissues. The fibers were not found in the mesothelial proliferative lesions themselves. In the pleural cavity, abundant inflammatory cell infiltration, mainly composed of macrophages, was observed. Conditioned cell culture media of macrophages treated with multi-walled carbon nanotubes and crocidolite and the supernatants of pleural cavity lavage fluid from the dosed rats increased mesothelial cell proliferation in vitro, suggesting that mesothelial proliferative lesions were induced by inflammatory events in the lung and pleural cavity and likely mediated by macrophages. In conclusion, intrapulmonary administration of multi-walled carbon nanotubes, like asbestos, induced mesothelial proliferation potentially associated with mesothelioma development.
多壁碳纳米管具有与石棉相似的纤维结构，注入腹腔时会诱发间皮瘤。本研究通过气管内给药探讨了多壁碳纳米管经肺进入体内是否会诱导间皮损伤。雄性 F344 大鼠经气管内喷雾，9 天内 5 次给予 0.5ml 浓度为 500μg/ml 的多壁碳纳米管或青石棉混悬液。随后收集胸腔灌洗液、肺脏和胸壁。多壁碳纳米管和青石棉主要存在于肺泡巨噬细胞和纵隔淋巴结中。重要的是，纤维也存在于胸腔灌洗液的细胞沉淀中，主要是巨噬细胞。多壁碳纳米管和青石棉处理均可诱导内脏间皮的增生性增殖病变，其增殖细胞核抗原指数约为载体对照组的 10 倍。增生性病变与炎症细胞浸润和炎症诱导的胸膜组织纤维化病变有关。纤维本身并未出现在间皮增生性病变中。在胸腔中，观察到大量炎症细胞浸润，主要为巨噬细胞。经多壁碳纳米管和青石棉处理的巨噬细胞的条件培养基以及来自给药大鼠的胸腔灌洗液上清液均可在体外增加间皮细胞增殖，提示肺和胸腔中的炎症事件诱导了间皮增生性病变，可能由巨噬细胞介导。总之，肺内给予多壁碳纳米管，类似于石棉，可诱导间皮增殖，可能与间皮瘤的发生有关。
