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

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.

Download Full-text

Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00398.2014 ◽

2015 ◽

Vol 309 (1) ◽

pp. L27-L36 ◽

Cited By ~ 39

Author(s):

Thomas E. Sussan ◽

Sachin Gajghate ◽

Samit Chatterjee ◽

Pooja Mandke ◽

Sarah McCormick ◽

...

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Allergic Asthma ◽

Airway Epithelial Cells ◽

Lung Epithelial Cells ◽

Related Factor ◽

Airway Epithelial ◽

Zonula Occludens ◽

Lung Epithelial ◽

Zonula Occludens 1

Asthma development and pathogenesis are influenced by the interactions of airway epithelial cells and innate and adaptive immune cells in response to allergens. Oxidative stress is an important mediator of asthmatic phenotypes in these cell types. Nuclear erythroid 2-related factor 2 ( Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and environmental stress. We previously demonstrated that Nrf2-deficient mice have heightened susceptibility to asthma, including elevated oxidative stress, inflammation, mucus, and airway hyperresponsiveness (AHR) (Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. J Exp Med 202: 47–59, 2005). Here we dissected the role of Nrf2 in lung epithelial cells and tested whether genetic or pharmacological activation of Nrf2 reduces allergic asthma in mice. Cell-specific activation of Nrf2 in club cells of the airway epithelium significantly reduced allergen-induced AHR, inflammation, mucus, Th2 cytokine secretion, oxidative stress, and airway leakiness and increased airway levels of tight junction proteins zonula occludens-1 and E-cadherin. In isolated airway epithelial cells, Nrf2 enhanced epithelial barrier function and increased localization of zonula occludens-1 to the cell surface. Pharmacological activation of Nrf2 by 2-trifluoromethyl-2′-methoxychalone during the allergen challenge was sufficient to reduce allergic inflammation and AHR. New therapeutic options are needed for asthma, and this study demonstrates that activation of Nrf2 in lung epithelial cells is a novel potential therapeutic target to reduce asthma susceptibility.

Download Full-text

Neurotrophins Produced by Airway Epithelial Cells Promote the Survival of Eosinophils During Allergic Asthma

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2005.12.245 ◽

2006 ◽

Vol 117 (2) ◽

pp. S61

Author(s):

C. Hahn ◽

A. Pyraesh ◽

H. Renz ◽

W.A. Nockher

Keyword(s):

Epithelial Cells ◽

Allergic Asthma ◽

Airway Epithelial Cells ◽

Airway Epithelial

Download Full-text

Group 2 Innate Lymphoid Cells and the House Dust Mite-Induced Asthma Mouse Model

Cells ◽

10.3390/cells9051178 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1178

Author(s):

Yuichiro Yasuda ◽

Tatsuya Nagano ◽

Kazuyuki Kobayashi ◽

Yoshihiro Nishimura

Keyword(s):

Epithelial Cells ◽

Mouse Model ◽

House Dust ◽

Innate Lymphoid Cells ◽

Airway Epithelial Cells ◽

Lymphoid Cells ◽

House Dust Mites ◽

Airway Epithelial ◽

Group 2 ◽

Asthma Mouse Model

Asthma is an important issue not only in health but also in economics worldwide. Therefore, asthma animal models have been frequently used to understand the pathogenesis of asthma. Recently, in addition to acquired immunity, innate immunity has also been thought to be involved in asthma. Among innate immune cells, group 2 innate lymphoid cells (ILC2s) have been considered to be crucial for eosinophilic airway inflammation by releasing T helper 2 cytokines. Moreover, house dust mites (HDMs) belonging to group 1 act on airway epithelial cells not only as allergens but also as cysteine proteases. The production of interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP) from airway epithelial cells was induced by the protease activity of HDMs. These cytokines activate ILC2s, and activated ILC2s produce IL-5, IL-9, IL-13, and amphiregulin. Hence, the HDM-induced asthma mouse model greatly contributes to understanding asthma pathogenesis. In this review, we highlight the relationship between ILC2s and the HDM in the asthma mouse model to help researchers and clinicians not only choose a proper asthma mouse model but also to understand the molecular mechanisms underlying HDM-induced asthma.

Download Full-text

Identification of histone acetylation in a murine model of allergic asthma by proteomic analysis

Experimental Biology and Medicine ◽

10.1177/1535370220980345 ◽

2020 ◽

pp. 153537022098034

Author(s):

Yuan Ren ◽

Menglu Li ◽

Shiyao Bai ◽

Lingfei Kong ◽

Xinming Su

Keyword(s):

Smooth Muscle ◽

Epithelial Cells ◽

Smooth Muscle Cells ◽

Histone Acetylation ◽

Allergic Asthma ◽

Inflammatory Cells ◽

Muscle Cells ◽

Airway Epithelial Cells ◽

Whole Body ◽

Airway Epithelial

The pathogenesis of asthma is closely related to histone acetylation modification, but the specific acetylation sites related to this process remain indistinct. Herein, our study sought to identify differentially modified acetylation sites and their expression distribution in cells involved in asthma in lung tissues. The airway hyper-responsiveness, inflammation, and remodeling were assessed by non-invasive whole-body plethysmography, ELISA, and hematoxylin-eosin staining to confirm the successful establishment of the allergic asthma model. Afterward, the differentially modified acetylation sites in asthmatic lung tissues were identified and validated by using proteomics and western blotting, respectively. The immunohistochemistry analysis was applied to reveal the distribution of identified acetylation sites in asthmatic lung tissues. A total of 15 differentially modified acetylation sites, including 13 upregulated (H3K9ac, H3K14ac, H3K18ac, H3K23ac,H3K27ac, H3K36ac, H2B1KK120ac, H2B2BK20ac, H2BK16ac, H2BK20ac, H2BK108ac, H2BK116ac, and H2BK120ac) and 2 downregulated (H2BK5ac and H2BK11ac) sites were identified and validated. Furthermore, immunohistochemical staining of lung tissues showed that nine of the identified histone acetylation sites (H2BK5, H2BK11, H3K18, H2BK116, H2BK20, H2BK120, H3K9, H3K36, and H3K27) were differentially expressed in airway epithelial cells, and the acetylation of identified H3 histones were observed in both eosinophil and perivascular inflammatory cells. Additionally, differential expression of histone acetylation sites was also observed in nucleus of airway epithelial cells, vascular smooth muscle cells, perivascular inflammatory cells, and airway smooth muscle cells. In conclusion, we identified potential acetylation sites associated with asthma pathogenesis. These findings may contribute greatly in the search for therapeutic approaches for allergic asthma.

Download Full-text

A Long Noncoding RNA Antisense to ICAM-1 Is Involved in Allergic Asthma Associated Hyperreactive Mucous Response of Airway Epithelial Cells

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7398 ◽

2020 ◽

Author(s):

D. Devadoss ◽

G. Daly ◽

M. Manevski ◽

D. Houserova ◽

S.S. Hussain ◽

...

Keyword(s):

Epithelial Cells ◽

Allergic Asthma ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Airway Epithelial Cells ◽

Airway Epithelial

Download Full-text

Kaempferol Suppresses Eosionphil Infiltration and Airway Inflammation in Airway Epithelial Cells and in Mice with Allergic Asthma

Journal of Nutrition ◽

10.3945/jn.111.150748 ◽

2011 ◽

Vol 142 (1) ◽

pp. 47-56 ◽

Cited By ~ 63

Author(s):

Ju-Hyun Gong ◽

Daekeun Shin ◽

Seon-Young Han ◽

Jung-Lye Kim ◽

Young-Hee Kang

Keyword(s):

Epithelial Cells ◽

Airway Inflammation ◽

Allergic Asthma ◽

Airway Epithelial Cells ◽

Airway Epithelial

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms22189924 ◽

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.

Download Full-text