Role of p53 in the chronic pulmonary immune response to tangled or rod-like multi-walled carbon nanotubes

Abstract

The fiber-like shape of multi-walled carbon nanotubes (MWCNTs) is reminiscent of asbestos, suggesting they pose similar health hazards when inhaled, including pulmonary fibrosis and mesothelioma. Mice deficient in the tumor suppressor p53 are susceptible to carcinogenesis. However, the chronic pathologic effect of MWCNTs delivered to the lungs of p53 heterozygous (p53^+/−) mice has not been investigated. We hypothesized that p53^+/− mice would be susceptible to lung tumor development after exposure to either tangled (t-) or rod-like (r-) MWCNTs. Wild-type (p53^+/+) or p53^+/− mice were exposed to MWCNTs (1 mg/kg) via oropharyngeal aspiration weekly over four consecutive weeks and evaluated for cellular and pathologic outcomes 11-months post-initial exposure. No lung or pleural tumors were observed in p53^+/+ or p53^+/− mice exposed to either t- or rMWCNTs. In comparison to tMWCNTs, the rMWCNTs induced the formation of larger granulomas, a greater number of lymphoid aggregates and greater epithelial cell hyperplasia in terminal bronchioles in both p53^+/− and p53^+/+ mice. A constitutively larger area of CD45R⁺/CD3⁺ lymphoid tissue was observed in p53^+/− mice compared to p53^+/+ mice. Importantly, p53^+/− mice had larger granulomas induced by rMWCNTs as compared to p53^+/+ mice. These findings indicate that a combination of p53 deficiency and physicochemical characteristics including nanotube geometry are factors in susceptibility to MWCNT-induced lymphoid infiltration and granuloma formation.

Keywords:

• Caron nanotubes
• immunotoxicology
• cancer
• granuloma
• p53

Acknowledgments

We are grateful for the help of Dr. Erinn Needham-Dandley for her expertise in TEM imaging of the as purchased MWCNTs.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by NIEHS R01ES020897 (to J.C.B., K.S.D., E.A.A., M.D.I., K.A.S., E.A.T. and A.J.T.), NIEHS Training Grant: T32 ES007046 (to K.S.D. and M.D.I.), and NIEHS P30 ES025128 (to D.A.T.). MFC was supported by the National Institute of Environmental Health Sciences Intramural Program. LMS, DWP and AFH were supported by the National Institute for Occupational Safety and Health. The findings and conclusions of this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.