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

2021 ◽  
Vol 22 (18) ◽  
pp. 9924
Author(s):  
Je-Oh Lim ◽  
Se-Jin Lee ◽  
Woong-Il Kim ◽  
So-Won Pak ◽  
Changjong Moon ◽  
...  
Keyword(s):  
Titanium Dioxide ◽  
Epithelial Cells ◽  
Mouse Model ◽  
Titanium Dioxide Nanoparticles ◽  
B Cell Lymphoma ◽  
Airway Epithelial Cells ◽  
Consumer Products ◽  
Airway Epithelial ◽  
Mucus Production ◽  
Apoptosis Pathway

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.

scholarly journals Titanium dioxide nanoparticles exacerbate allergic airway inflammation via TXNIP upregulation in a mouse model of asthma

2021 ◽  
Author(s):  
Je-Oh Lim ◽  
Se-Jin Lee ◽  
Woong-Il Kim ◽  
So-Won Pak ◽  
Changjong Moon ◽  
...  
Keyword(s):  
Titanium Dioxide ◽  
Epithelial Cells ◽  
Mouse Model ◽  
Inflammatory Mediators ◽  
Titanium Dioxide Nanoparticles ◽  
B Cell Lymphoma ◽  
Airway Epithelial Cells ◽  
Consumer Products ◽  
Airway Epithelial ◽  
Apoptosis Pathway

Abstract Background Titanium dioxide nanoparticles (TiO2NPs) are widely used in the fields of industry and medicine and in various consumer products. With the increasing use of TiO2NPs, there has been an increase in the number of toxicity studies; however, studies investigating the mechanism underlying its toxicity are very rare. In this study, we evaluated the potential toxic effects of TiO2NPs exposure on the lungs as well as the development of asthma in ovalbumin (OVA)-induced mouse model of asthma. We also investigated the related toxic mechanism. Results TiO2NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number of inflammatory cells and levels of inflammatory mediators. Exposure of mice with OVA-induced asthma to TiO2NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with non-exposed mice with asthma. This was also accompanied by an increase in inflammatory cell infiltration and mucus production in the lung tissues. TiO2NPs also decreased the expression of B-cell lymphoma 2 (Bcl2) and increased the expression of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 in the lungs of asthmatic mice compared with those of 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 IL-1β, IL-6, and TNF-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO2NPs treatment were significantly decreased by TXNIP knockdown in the airway epithelial cells. Conclusion Taken together, TiO2NPs 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 mechanism underlying TiO2NPs-mediated respiratory toxicity.

scholarly journals Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma

2017 ◽  
Vol 199 (1) ◽  
pp. 48-61 ◽  
Author(s):  
Carina Klaßen ◽  
Anna Karabinskaya ◽  
Lien Dejager ◽  
Sabine Vettorazzi ◽  
Justine Van Moorleghem ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Allergic Asthma ◽  
Airway Epithelial Cells ◽  
Airway Epithelial

Induction of Oxidative DNA Damage and Epithelial Mesenchymal Transitions in Small Airway Epithelial Cells Exposed to Cosmetic Aerosols

2020 ◽  
Vol 177 (1) ◽  
pp. 248-262
Author(s):  
Kaitlin M Pearce ◽  
Imoh Okon ◽  
Christa Watson-Wright
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Epithelial Cells ◽  
Oxidative Dna Damage ◽  
Airway Epithelial Cells ◽  
Consumer Products ◽  
Small Airway ◽  
Airway Epithelial ◽  
Western Blots ◽  
Small Airway Epithelial Cells

Abstract Engineered metal nanoparticles (ENPs) are frequently incorporated into aerosolized consumer products, known as nano-enabled products (NEPs). Concern for consumer pulmonary exposures grows as NEPs produce high concentrations of chemically modified ENPs. A significant knowledge gap still exists surrounding NEP aerosol respiratory effects as previous research focuses on pristine/unmodified ENPs. Our research evaluated metal-containing aerosols emitted from nano-enabled cosmetics and their induction of oxidative stress and DNA damage, which may contribute to epithelial mesenchymal transitions (EMT) within primary human small airway epithelial cells. We utilized an automated NEP generation system to monitor and gravimetrically collect aerosols from two aerosolized cosmetic lines. Aerosol monitoring data were inputted into modeling software to determine potential inhaled dose and in vitro concentrations. Toxicological profiles of aerosols and comparable pristine ENPs (TiO2 and Fe2O3) were used to assess reactive oxygen species and oxidative stress by fluorescent-based assays. Single-stranded DNA (ssDNA) damage and 8-oxoguanine were detected using the CometChip assay after 24-h exposure. Western blots were conducted after 21-day exposure to evaluate modulation of EMT markers. Results indicated aerosols possessed primarily ultrafine particles largely depositing in tracheobronchial lung regions. Significant increases in oxidative stress, ssDNA damage, and 8-oxoguanine were detected post-exposure to aerosols versus pristine ENPs. Western blots revealed statistically significant decreases in E-cadherin and increases in vimentin, fascin, and CD44 for two aerosols, indicating EMT. This work suggests certain prolonged NEP inhalation exposures cause oxidative DNA damage, which may play a role in cellular changes associated with reduced respiratory function and should be of concern.

TMEM16A Mediates Mucus Production in Human Airway Epithelial Cells

2021 ◽  
Vol 64 (1) ◽  
pp. 50-58
Author(s):  
Inês Cabrita ◽  
Roberta Benedetto ◽  
Podchanart Wanitchakool ◽  
Joana Lerias ◽  
Raquel Centeio ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Mucus Production ◽  
Human Airway ◽  
Human Airway Epithelial Cells

scholarly journals β2-Adrenoceptor signaling in airway epithelial cells promotes eosinophilic inflammation, mucous metaplasia, and airway contractility

2017 ◽  
Vol 114 (43) ◽  
pp. E9163-E9171 ◽  
Author(s):  
Long P. Nguyen ◽  
Nour A. Al-Sawalha ◽  
Sergio Parra ◽  
Indira Pokkunuri ◽  
Ozozoma Omoluabi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelium ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Airway Smooth Muscle Cells ◽  
Airway Epithelial ◽  
Eosinophilic Inflammation ◽  
Mucus Production ◽  
Asthma Phenotype ◽  
Transgenic Expression

The mostly widely used bronchodilators in asthma therapy are β2-adrenoreceptor (β2AR) agonists, but their chronic use causes paradoxical adverse effects. We have previously determined that β2AR activation is required for expression of the asthma phenotype in mice, but the cell types involved are unknown. We now demonstrate that β2AR signaling in the airway epithelium is sufficient to mediate key features of the asthmatic responses to IL-13 in murine models. Our data show that inhibition of β2AR signaling with an aerosolized antagonist attenuates airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus-production responses to IL-13, whereas treatment with an aerosolized agonist worsens these phenotypes, suggesting that β2AR signaling on resident lung cells modulates the asthma phenotype. Labeling with a fluorescent β2AR ligand shows the receptors are highly expressed in airway epithelium. In β2AR−/− mice, transgenic expression of β2ARs only in airway epithelium is sufficient to rescue IL-13–induced AHR, inflammation, and mucus production, and transgenic overexpression in WT mice exacerbates these phenotypes. Knockout of β-arrestin-2 (βarr-2−/−) attenuates the asthma phenotype as in β2AR−/− mice. In contrast to eosinophilic inflammation, neutrophilic inflammation was not promoted by β2AR signaling. Together, these results suggest β2ARs on airway epithelial cells promote the asthma phenotype and that the proinflammatory pathway downstream of the β2AR involves βarr-2. These results identify β2AR signaling in the airway epithelium as capable of controlling integrated responses to IL-13 and affecting the function of other cell types such as airway smooth muscle cells.

scholarly journals CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A

2021 ◽  
Vol 22 (10) ◽  
pp. 5133
Author(s):  
Raquel Centeio ◽  
Jiraporn Ousingsawat ◽  
Rainer Schreiber ◽  
Karl Kunzelmann
Keyword(s):  
Epithelial Cells ◽  
Goblet Cell ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Membrane Expression ◽  
Mucus Production ◽  
Ion Secretion ◽  
Airway Mucus ◽  
Goblet Cell Metaplasia

TMEM16A, a Ca2+-activated chloride channel (CaCC), and its regulator, CLCA1, are associated with inflammatory airway disease and goblet cell metaplasia. CLCA1 is a secreted protein with protease activity that was demonstrated to enhance membrane expression of TMEM16A. Expression of CLCA1 is particularly enhanced in goblet cell metaplasia and is associated with various lung diseases. However, mice lacking expression of CLCA1 showed the same degree of mucous cell metaplasia and airway hyperreactivity as asthmatic wild-type mice. To gain more insight into the role of CLCA1, we applied secreted N-CLCA1, produced in vitro, to mice in vivo using intratracheal instillation. We observed no obvious upregulation of TMEM16A membrane expression by CLCA1 and no differences in ATP-induced short circuit currents (Iscs). However, intraluminal mucus accumulation was observed by treatment with N-CLCA1 that was not seen in control animals. The effects of N-CLCA1 were augmented in ovalbumin-sensitized mice. Mucus production induced by N-CLCA1 in polarized BCi-NS1 human airway epithelial cells was dependent on TMEM16A expression. IL-13 upregulated expression of CLCA1 and enhanced mucus production, however, without enhancing purinergic activation of Isc. In contrast to polarized airway epithelial cells and mouse airways, which express very low levels of TMEM16A, nonpolarized airway cells express large amounts of TMEM16A protein and show strong CaCC. The present data show an only limited contribution of TMEM16A to airway ion secretion but suggest a significant role of both CLCA1 and TMEM16A for airway mucus secretion.

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