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.

中文翻译：

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巨噬细胞极化和活化的多壁碳纳米管诱导的肺部炎症和纤维化的界面。

肺部接触碳纳米管（CNTs）会诱发肺部纤维化病变，表现出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人类暴露的健康问题。碳纳米管诱导的纤维化作用的潜在机制尚不清楚。众所周知，巨噬细胞通过其独特的亚群在免疫调节和纤维化发展中起重要作用。在这里，我们研究了暴露于多壁CNT（MWCNT）的小鼠肺中的巨噬细胞极化和激活。雄性C57BL / 6J小鼠经口咽抽吸以MWCNT（XNRI MWNT-7）处理，每只小鼠40μg（〜1.86 mg / kg体重）。该治疗刺激了显着的急性炎症和纤维化反应。而且，它以明显的时间依赖性诱导了巨噬细胞的明显富集和极化，M1和M2种群显着增加。M1极化的诱导在第1天就很明显，在第3天达到峰值，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天明显升高，并在第7天一直维持在高水平。M1和M2巨噬细胞被MWCNTs功能性激活，如它们独特的功能性表达所表明的那样。标记，例如iNOS和ARG1，其时程分别平行于M1和M2极化。分子分析显示，MWCNTs增强了特定的STAT和IRF信号通路，以调节肺中的M1和M2极化。