a Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division , National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention , Morgantown , WV , USA.
Nanotoxicology. 2018 Mar;12(2):153-168. doi: 10.1080/17435390.2018.1425501. Epub 2018 Jan 16.
Pulmonary exposure to carbon nanotubes (CNTs) induces fibrosing lesions in the lungs that manifest rapid-onset inflammatory and fibrotic responses, leading to chronic fibrosis in animals and health concerns in exposed humans. The mechanisms underlying CNT-induced fibrogenic effects remain undefined. Macrophages are known to play important roles in immune regulation and fibrosis development through their distinct subsets. Here we investigated macrophage polarization and activation in mouse lungs exposed to multi-walled CNTs (MWCNTs). Male C57BL/6J mice were treated with MWCNTs (XNRI MWNT-7) at 40 μg per mouse (∼1.86 mg/kg body weight) by oropharyngeal aspiration. The treatment stimulated prominent acute inflammatory and fibrotic responses. Moreover, it induced pronounced enrichment and polarization of macrophages with significantly increased M1 and M2 populations in a time-dependent manner. Induction of M1 polarization was apparent on day 1 with a peak on day 3, but declined rapidly thereafter. On the other hand, the M2 polarization was induced on day 1 modestly, but was remarkably elevated on day 3 and maintained at a high level through day 7. M1 and M2 macrophages were functionally activated by MWCNTs as indicated by the expression of their distinctive functional markers, such as iNOS and ARG1, with time courses parallel to M1 and M2 polarization, respectively. Molecular analysis revealed MWCNTs boosted specific STAT and IRF signaling pathways to regulate M1 and M2 polarization in the lungs. These findings suggest a new mechanistic connection between inflammation and fibrosis induced by MWCNTs through the polarization and activation of macrophages during MWCNT-induced lung pathologic response.
肺部暴露于碳纳米管（CNTs）会导致肺部出现纤维病变，表现为快速发作的炎症和纤维化反应，从而导致动物的慢性纤维化和暴露于 CNT 的人类的健康问题。CNT 诱导的纤维发生效应的机制仍未定义。巨噬细胞通过其不同的亚群，已知在免疫调节和纤维化发展中发挥重要作用。在这里，我们研究了暴露于多壁 CNT（MWCNT）的小鼠肺部中巨噬细胞的极化和激活。雄性 C57BL/6J 小鼠通过口咽吸入法用 MWCNT（XNRI MWNT-7）处理，每只小鼠 40μg（约 1.86mg/kg 体重）。该处理刺激了明显的急性炎症和纤维化反应。此外，它还诱导了巨噬细胞的明显富集和极化，并且 M1 和 M2 群体的数量随着时间的推移呈显著增加。M1 极化在第 1 天明显诱导，在第 3 天达到高峰，但此后迅速下降。另一方面，M2 极化在第 1 天适度诱导，但在第 3 天显著升高，并在第 7 天保持高水平。MWCNT 诱导 M1 和 M2 巨噬细胞的功能激活，如 iNOS 和 ARG1 的表达，其特征性功能标志物，分别与 M1 和 M2 极化的时间过程平行。分子分析表明，MWCNT 通过调节肺部中 M1 和 M2 极化的特定 STAT 和 IRF 信号通路来增强炎症和纤维化。这些发现表明，MWCNT 诱导的肺部病理反应中，巨噬细胞的极化和激活是 MWCNT 诱导的炎症和纤维化的一种新的机制联系。
