149 Chronic Immunotoxicity of Multi-Walled Carbon Nanotubes on Macrophages via MMP-12

Abstract

Abstract Background The toxicological effects of nanomaterials, such as multi-walled carbon nanotubes (MWCNTs), on the immune system are considerably understood. However, the precise relationship between long-term exposure to MWCNTs and chronic inflammation remains unclear. Methods and Finding In this study, exposure to Taquann-treated MWCNTs (T-CNTs) was performed using aerosols generated in an inhalation chamber. At 12 months after T-CNT exposure, alveolar inflammation with macrophage accumulation and hypertrophy of the alveolar walls were observed. The fibrotic lesions were enhanced by T-CNT exposure. The cell surface phenotype of macrophages in the bronchoalveolar lavage fluid was shifted to the M1 macrophage phenotype. In addition, the alveolar macrophages of T-CNT-exposed mice produced matrix metalloprotinase-12 (MMP-12). By contrast, a mouse model of chronic peritonitis was also established using intraperitoneal injection of T-CNTs with high dispersion efficiency. Chronic peritonitis with fibrosis was observed in T-CNT-injected mice, but not in Taquann-treated TiO2-injected mice. In vivo and in vitro experiments showed that MMP-12 of macrophages was upregulated by T-CNT to enhance fibroblast activation and profibrotic molecule expression in fibroblasts. In addition, T-CNT-induced peritonitis reduced MMP-12 expression in Nfκb1−/− mice, suggesting that MMP-12-producing macrophages play a key role in chronic inflammation due to T-CNT exposure though NF-κB activation. Conclusion These results using the two models suggest that T-MWCNT exposure promoted chronic inflammation and fibrotic lesion formation in profibrotic macrophages via MMP12 for prolonged periods. The results of this study could be helpful in understanding the molecular toxicity of nanomaterial and chronic inflammation.