Lim Je-Oh, Lee Se-Jin, Kim Woong-Il, Pak So-Won, Moon Changjong, Shin In-Sik, Heo Jeong-Doo, Ko Je-Won, Kim Jong-Choon
College of Veterinary Medicine (BK21 FOUR Program), Chonnam National University, Gwangju 61186, Korea.
Bioenvironmental Science & Technology Division, Korea Institute of Toxicology, Jinju 52834, Korea.
Int J Mol Sci. 2021 Sep 14;22(18):9924. doi: 10.3390/ijms22189924.
Titanium dioxide nanoparticles (TiONPs) 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 TiONPs 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. TiONPs 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 TiONPs 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, TiONPs 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. TiONPs 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 TiONP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiONP 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 TiONP-mediated respiratory toxicity.
二氧化钛纳米颗粒（TiONPs）广泛应用于工业、医药领域以及各类消费品中，其使用量的不断增加使得毒性研究的数量也随之增多；然而，探究潜在毒性机制的研究却较为罕见。在本研究中，我们通过卵清蛋白（OVA）诱导的小鼠哮喘模型，评估了暴露于TiONPs对肺部的潜在毒性作用以及哮喘的发展情况。此外，我们还研究了相关的毒性机制。TiONPs通过加剧炎症反应导致肺部毒性，炎症细胞数量和炎症介质水平的增加分别表明了这一点。与未暴露于TiONPs的哮喘小鼠相比，暴露于TiONPs的OVA诱导哮喘小鼠的炎症介质、细胞因子和气道高反应性显著增加。这还伴随着肺组织中炎症细胞浸润和黏液分泌的增加。此外，与未暴露于TiONPs的哮喘小鼠相比，TiONPs降低了哮喘小鼠肺部B细胞淋巴瘤2（Bcl2）的表达，而硫氧还蛋白相互作用蛋白（TXNIP）、磷酸化凋亡信号调节激酶1、Bcl2相关X蛋白和裂解的半胱天冬酶3的表达则有所升高。这些反应与使用人气道上皮细胞获得的体外结果一致。与未处理的细胞相比，经TiONPs处理的细胞白细胞介素（IL）-1β、IL-6和肿瘤坏死因子-α的mRNA和蛋白表达增加，且TXNIP信号传导升高。此外，气道上皮细胞中TXNIP基因敲低可显著降低TiONP处理诱导的病理生理变化。总体而言，暴露于TiONPs会引起呼吸道的毒理学变化，并通过激活TXNIP-凋亡途径加剧哮喘的发展。这些结果为TiONP介导的呼吸毒性潜在机制提供了见解。
