Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis
Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis
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DOI：
10.1073/pnas.1110013108
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发表时间：
2011-12-06
影响因子：
11.1
通讯作者：
Toyokuni, Shinya
中科院分区：
文献类型：
--
作者：
Nagai, Hirotaka;Okazaki, Yasumasa;Toyokuni, Shinya
多壁碳纳米管（MWCNTs）在工程和材料科学领域具有广泛的应用前景。然而，由于其针状形状和高耐久性，人们担心MWCNTs可能诱发石棉样致病性。尽管最近的研究表明，MWCNTs可诱导多种类型的反应，但确定MWCNTs在间皮细胞中的细胞毒性和致癌性的理化特征尚不清楚。在这里，我们发现非功能化的MWCNTs对人间皮细胞的有害作用与它们对细胞膜的直径依赖性刺穿有关。高结晶度的薄MWCNTs（直径约为50 nm）在体外表现出刺穿间皮细胞膜和细胞毒性，随后在体内表现出致炎和致间皮瘤性。相比之下，厚的（直径约为150nm）或缠结的（直径约为2- 20nm） MWCNTs毒性、致炎性和致癌性较低。薄的和厚的MWCNTs同样影响巨噬细胞。MWCNTs诱导的间皮瘤共享Cdkn2a/2b肿瘤抑制基因的纯合缺失，类似于石棉诱导的间皮瘤。因此，我们提出，薄和厚MWCNTs对间皮的直接损伤程度不同是致炎性和致癌性程度的原因。这项工作表明，控制MWCNTs的直径可以减少对人类健康的潜在危害。
Multiwalled carbon nanotubes (MWCNTs) have the potential for widespread applications in engineering and materials science. However, because of their needle-like shape and high durability, concerns have been raised that MWCNTs may induce asbestos-like pathogenicity. Although recent studies have demonstrated that MWCNTs induce various types of reactivities, the physicochemical features of MWCNTs that determine their cytotoxicity and carcinogenicity in mesothelial cells remain unclear. Here, we showed that the deleterious effects of nonfunctionalized MWCNTs on human mesothelial cells were associated with their diameter-dependent piercing of the cell membrane. Thin MWCNTs (diameter similar to 50 nm) with high crystallinity showed mesothelial cell membrane piercing and cytotoxicity in vitro and subsequent inflammo-genicity and mesotheliomagenicity in vivo. In contrast, thick (diameter similar to 150 nm) or tangled (diameter similar to 2-20 nm) MWCNTs were less toxic, inflammogenic, and carcinogenic. Thin and thick MWCNTs similarly affected macrophages. Mesotheliomas induced by MWCNTs shared homozygous deletion of Cdkn2a/2b tumor suppressor genes, similar to mesotheliomas induced by asbestos. Thus, we propose that different degrees of direct mesothelial injury by thin and thick MWCNTs are responsible for the extent of inflammogenicity and carcinogenicity. This work suggests that control of the diameter of MWCNTs could reduce the potential hazard to human health.