Exposure to Multiwall Carbon Nanotubes Promotes Fibrous Proliferation by Production of Matrix Metalloproteinase-12 via NF-κB Activation in Chronic Peritonitis

Takaaki Tsunematsu; Rieko Arakaki; Mami Sato; Masako Saito; Kunihiro Otsuka; Yusuke Furukawa; Yuhji Taquahashi; Jun Kanno; Naozumi Ishimaru

doi:10.1016/j.ajpath.2022.07.009

Exposure to Multiwall Carbon Nanotubes Promotes Fibrous Proliferation by Production of Matrix Metalloproteinase-12 via NF-κB Activation in Chronic Peritonitis

Am J Pathol. 2022 Nov;192(11):1559-1572. doi: 10.1016/j.ajpath.2022.07.009. Epub 2022 Aug 10.

Authors

Takaaki Tsunematsu¹, Rieko Arakaki¹, Mami Sato¹, Masako Saito¹, Kunihiro Otsuka¹, Yusuke Furukawa², Yuhji Taquahashi², Jun Kanno², Naozumi Ishimaru³

Affiliations

¹ Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
² Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Kawasaki, Japan.
³ Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan. Electronic address: ishimaru.n@tokushima-u.ac.jp.

PMID: 35963465
DOI: 10.1016/j.ajpath.2022.07.009

Abstract

The toxicologic effects of nanomaterials, such as carbon nanotubes (CNTs), on the immune system are understood well. However, the precise relationship between long-term exposure to CNTs and chronic inflammation remains unclear. In this study, a mouse model of chronic peritonitis was established using i.p. injection of multiwalled CNTs treated by the Taquann method with high dispersion efficiency. Chronic peritonitis with fibrosis was observed in Taquann-treated multiwalled CNT (T-CNT)-injected mice, but not in Taquann-treated titanium dioxide-injected mice. In vivo and in vitro experiments showed that matrix metalloproteinase-12 (MMP-12) of macrophages was up-regulated 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 through NF-κB activation. The results of this study could be helpful in understanding the molecular toxicity of nanomaterial and chronic inflammation.