Nickel Nanoparticles cause exaggerated lung and airway remodeling in mice lacking the T-box transcription factor, TBX21 (T-bet)

Ellen E Glista-Baker,Brian C Sayers,Alexia J Taylor,James C Bonner,Elizabeth A Thompson

doi:10.1186/1743-8977-11-7

Ellen E Glista-Baker, Brian C Sayers + Show 3 more

Open Access

https://doi.org/10.1186/1743-8977-11-7

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Abstract

BackgroundNickel nanoparticles (NiNPs) are increasingly used in a variety of industrial applications, including the manufacturing of multi-walled carbon nanotubes (MWCNTs). While occupational nickel exposure is a known cause of pulmonary alveolitis, fibrosis, and cancer, the health risks of NiNPs are not well understood, especially in susceptible individuals such as asthmatics. The T-box transcription factor Tbx21 (T-bet) maintains Th1 cell development and loss of T-bet is associated with a shift towards Th2 type allergic airway inflammation that characterizes asthma. The purpose of this study was to determine the role of T-bet in susceptibility to lung remodeling by NiNPs or MWCNTs.MethodsWild-type (WT) and T-bet-/- mice were exposed to NiNPs or MWCNTs (4 mg/kg) by oropharyngeal aspiration (OPA). Necropsy was performed at 1 and 21 days. Bronchoalveolar lavage fluid (BALF) was collected for differential counting of inflammatory cells and for measurement of cytokines by ELISA. The left lung was collected for histopathology. The right lung was analyzed for cytokine or mucin (MUC5AC and MUC5B) mRNAs.ResultsMorphometry of alcian-blue/periodic acid Schiff (AB/PAS)-stained lung tissue showed that NiNPs significantly increased mucous cell metaplasia in T-bet-/- mice at 21 days (p < 0.001) compared to WT mice, and increased MUC5AC and MUC5B mRNAs (p < 0.05). MWCNTs also increased mucous cell metaplasia in T-bet-/- mice, but to a lesser extent than NiNPs. Chronic alveolitis was also increased by NiNPs, but not MWCNTs, in T-bet-/- mice compared to WT mice at 21 days (P < 0.001). NiNPs also increased IL-13 and eosinophils (p < 0.001) in BALF from T-bet-/- mice after 1 day. Interestingly, the chemokine CCL2 in the BALF of T-bet-/- mice was increased at 1 and 21 days (p < 0.001 and p < 0.05, respectively) by NiNPs, and to a lesser extent by MWCNTs at 1 day. Treatment of T-bet-/- mice with a monoclonal anti-CCL2 antibody enhanced NiNP-induced mucous cell metaplasia and MUC5AC mRNA levels (p < 0.05), yet marginally reduced NiNP-induced alveolitis.ConclusionThese findings identify T-bet as a potentially important susceptibility factor for NiNP exposure and to a lesser extent for MWCNT exposure, and suggests that individuals with asthma are at greater risk.

Highlights

Nickel nanoparticles (NiNPs) are increasingly used in a variety of industrial applications, including the manufacturing of multi-walled carbon nanotubes (MWCNTs)
Mucous cell metaplasia is amplified in T-box transcription factor TBX21 (T-bet) deficient mice after NiNP exposure Wild-type (WT) and T-bet knockout (T-bet−/−) mice were exposed to nickel nanoparticles (NiNPs) or multiwalled carbon nanotubes (MWCNTs) by oropharyngeal aspiration (OPA) and lung tissue was harvested 1 day or 21 days after initial exposure
Data from these measurements showed that NiNP exposure increased mucous cell metaplasia in WT or T-bet−/− mice at 1 day, this increase was not significant compared to controls or between genotypes (Figure 1A)

Summary

Introduction

Nickel nanoparticles (NiNPs) are increasingly used in a variety of industrial applications, including the manufacturing of multi-walled carbon nanotubes (MWCNTs). The T-box transcription factor Tbx (T-bet) maintains Th1 cell development and loss of T-bet is associated with a shift towards Th2 type allergic airway inflammation that characterizes asthma. Asthma is a chronic inflammatory disease of the airways that currently affects more than 25 million people in the United States and 300 million people worldwide [1] It is characterized by periods of acute bronchoconstriction defined by airway hyperresponsiveness, mucus hypersecretion, and airway remodeling that involves eosinophilic inflammation, subepithelial collagen deposition, airway smooth muscle cell hypertrophy and hyperplasia, and mucous cell metaplasia (a phenotypic shift of the mucus-producing airway epithelium from serous cells to mucus-laden goblet cells) [2]. The airways of asthmatics have been shown to have significantly less T-bet expression when compared to non-asthmatic lungs suggesting that T-bet−/− mice would be a useful Th2-mediated model of asthma [10]

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