Multi-walled carbon nanotubes elicit sustained pulmonary remodelling depending on gender rather than a functional Nrf2 status

Abstract

Rationale: Multi-walled carbon nanotubes (MWCNT) are nanomaterials that can cause pulmonary inflammation, tissue remodelling and profibrotic lesions. Redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2) is implicated in MWCNT-induced pulmonary damage whereas the impact of gender and sustained exposure are unknown. Therefore, our aim was to evaluate the pulmonary damaging effects of MWCNT in Nrf2-/- and Nrf2+/+ male and female mice after 60 days exposure. Methods: Female and male Nrf2-/- and +/+ mice aged 9-10 weeks were exposed to MWCNT (Mitsui) by a single pharyngeal aspiration of 40μl of 1mg/ml suspension per 20g body weight. After 60 days, animals were sacrificed to collect blood and lungs to analyse markers of pulmonary remodelling, oxidative stress and inflammation. Results: MWCNT exposure significantly increased interstitial fibrosis, granuloma lesions and bronchoalveolar hyperplasia in all groups. Gender significantly affected the interstitial lesions and fibrosis whereas Nrf2-status did not. MWCNT exposure significantly reduced systemic antioxidant capacity as well as pulmonary antioxidant levels in Nrf2 -/- males. Pulmonary inflammation was significantly enhanced in all MWCNT-treated mice irrespective of gender or genotype. Systemic inflammation was not significantly affected by MWCNT treatment although a trend was observed for elevated IL-10 plasma levels in Nrf-/- males (p=0.0053). Conclusion: MWCNT induce sustained pulmonary remodelling and inflammation in mice dependent of gender but independent of a functional Nrf2 suggesting that other not redox-regulated pathways may have a stronger impact on the pro-fibrotic effects of MWCNT.