Titanium Dioxide Nanoparticles Exacerbate Allergic Airway Inflammation via TXNIP Upregulation in a Mouse Model of Asthma.

Je-Oh Lim,Changjong Moon,So-Won Pak,Je-Won Ko,In-Sik Shin,Woong-Il Kim,Jong-Choon Kim,Jeong-Doo Heo,Se-Jin Lee

doi:10.3390/ijms22189924

Abstract

Titanium dioxide nanoparticles (TiO2NPs) are widely used in industrial and medicinal fields and in various consumer products, and their increasing use has led to an increase in the number of toxicity studies; however, studies investigating the underlying toxicity mechanism have been rare. In this study, we evaluated potential toxic effects of TiO2NPs exposure on lungs as well as the development of asthma through the ovalbumin (OVA)-induced mouse model of asthma. Furthermore, we also investigated the associated toxic mechanism. TiO2NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number and level of inflammatory cells and mediators, respectively. OVA-induced asthma exposed mice to TiO2NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with those in non-exposed asthmatic mice. This was also accompanied by increased inflammatory cell infiltration and mucus production in the lung tissues. Additionally, TiO2NPs decreased the expression of B-cell lymphoma 2 (Bcl2) and the expressions of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 were escalated in the lungs of asthmatic mice compared with those in non-exposed asthmatic mice. These responses were consistent with in vitro results obtained using human airway epithelial cells. TiO2NPs treated cells exhibited an increase in the mRNA and protein expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO2NP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiO2NP exposure induced toxicological changes in the respiratory tract and exacerbated the development of asthma via activation of the TXNIP-apoptosis pathway. These results provide insights into the underlying mechanism of TiO2NP-mediated respiratory toxicity.

Highlights

Air pollutants such as yellow and fine dust, have become a critical social issue and are life-threatening to patients with respiratory diseases
There has been an increase in the number of patients with underlying respiratory diseases, a vulnerable subpopulation who warrant consideration when evaluating the potential respiratory of various substanceswith
There has been an increase in toxicity the number of patients respiratory examine the effect of TiO2 NPs on asthma exacerbation and to elucidate its underlying diseases, a vulnerable subpopulation who warrant consideration when evaluating the pomechanism

Summary

Introduction

Air pollutants such as yellow and fine dust, have become a critical social issue and are life-threatening to patients with respiratory diseases. Several studies [1,2,3,4] have reported that titanium dioxide nanoparticles (TiO2 NPs), components of Asian dust and air pollutants, exacerbate respiratory distress [1,2,3,4]. Of the known respiratory diseases, asthma is an inflammatory disease of the respiratory airways that affects approximately 300 million people globally [7] It is characterized by excessive inflammation of bronchi and obstruction of the airflow due to increased immune responses, resulting in varying respiratory symptoms, mainly difficulty in breathing, wheezing, coughing, and tightness in the chest [3,8,9]. Previous studies have shown that fine dust and air pollutants aggravate asthma; the underlying toxicity mechanism is not well established

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