Titanium Dioxide Nanoparticles Exacerbate Respiratory Syncytial Virus-Induced Airway Epithelial Barrier Dysfunction

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children worldwide. While most develop a mild, self-limiting illness, some develop severe acute lower respiratory infection and persistent airway disease. Exposure to ambient particulate matter has been linked to asthma, bronchitis, and viral infection in multiple epidemiological studies. We hypothesized that coexposure to nanoparticles worsens RSV-induced airway epithelial barrier dysfunction. Bronchial epithelial cells were incubated with titanium dioxide nanoparticles (TiO2-NP) or a combination of TiO2-NP and RSV. Structure and function of epithelial cell barrier were analyzed. Viral titer and the role of reactive oxygen species (ROS) generation were evaluated. In vivo, mice were intranasally incubated with TiO2-NP, RSV, or a combination. Lungs and bronchoalveolar lavage (BAL) fluid were harvested for analysis of airway inflammation and apical junctional complex (AJC) disruption. RSV-induced AJC disruption was amplified by TiO2-NP. Nanoparticle exposure increased viral infection in epithelial cells. TiO2-NP induced generation of ROS, and pretreatment with antioxidant, N-acetylcysteine, reversed said barrier dysfunction. In vivo, RSV-induced injury and AJC disruption were augmented in the lungs of mice given TiO2-NP. Airway inflammation was exacerbated, as evidenced by increased white blood cell infiltration into the BAL, along with exaggeration of peribronchial inflammation and AJC disruption. These data demonstrate that TiO2-NP exposure exacerbates RSV-induced AJC dysfunction and increases inflammation by mechanisms involving generation of ROS. Further studies are required to determine whether NP exposure plays a role in the health disparities of asthma and other lung diseases, and why some children experience more severe airway disease with RSV infection.

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Disruption of the airway epithelial barrier in a murine model of respiratory syncytial virus infection

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00345.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. L358-L368 ◽

Cited By ~ 4

Author(s):

Carrie C. Smallcombe ◽

Debra T. Linfield ◽

Terri J. Harford ◽

Vladimir Bokun ◽

Andrei I. Ivanov ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Epithelial Cells ◽

Tight Junction ◽

Epithelial Barrier ◽

Airway Epithelial ◽

Barrier Dysfunction ◽

Rsv Infection ◽

Syncytial Virus

Respiratory syncytial virus (RSV) is a major cause of hospitalization for infants and young children worldwide. RSV is known to infect epithelial cells and increase the permeability of model airway epithelial monolayers in vitro. We hypothesized that RSV infection also induces airway barrier dysfunction in vivo. C57BL/6 mice were intranasally inoculated with RSV, and on day 4 post-inoculation were examined for viral replication, lung inflammation, and barrier integrity as well as the structure and molecular composition of epithelial junctions. In parallel, primary mouse tracheal epithelial cells (mTEC) were cultured for in vitro studies. RSV-infected mice lost weight and showed significant peribronchial inflammation compared with noninfected controls and UV-inactivated RSV-inoculated animals. RSV infection increased the permeability of the airway epithelial barrier and altered the molecular composition of epithelial tight junctions. The observed RSV-induced barrier disruption was accompanied by decreased expression of several tight-junction proteins and accumulation of cleaved extracellular fragments of E-cadherin in bronchoalveolar lavage and mTEC supernatants. Similarly, in vitro RSV infection of mTEC monolayers resulted in enhanced permeability and disruption of tight-junction structure. Furthermore, incubation of mTEC monolayers with a recombinant fragment of E-cadherin caused tight-junction disassembly. Taken together, these data indicate that RSV infection leads to airway barrier dysfunction in vivo, mediated by either decreased expression or cleavage of junctional proteins. Our observations provide further insights into the pathophysiology of RSV infection and provide a rationale for development of barrier-protecting agents to alleviate the pathogenic effects of RSV infection.

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The role of secreted Hsp90α in HDM-induced asthmatic airway epithelial barrier dysfunction

BMC Pulmonary Medicine ◽

10.1186/s12890-019-0938-z ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Cuiping Ye ◽

Chaowen Huang ◽

Mengchen Zou ◽

Yahui Hu ◽

Lishan Luo ◽

...

Keyword(s):

Barrier Function ◽

Epithelial Barrier ◽

Airway Epithelial ◽

Barrier Dysfunction ◽

Epithelial Barrier Function ◽

Asthmatic Airway ◽

Epithelial Barrier Dysfunction

Abstract Background The dysfunction of airway epithelial barrier is closely related to the pathogenesis of asthma. Secreted Hsp90α participates in inflammation and Hsp90 inhibitor protects endothelial dysfunction. In the current study, we aimed to explore the role of secreted Hsp90α in asthmatic airway epithelial barrier function. Methods Male BALB/c mice were sensitized and challenged with HDM to generate asthma model. The 16HBE and Hsp90α-knockdown cells were cultured and treated according to the experiment requirements. Transepithelial Electric Resistance (TEER) and permeability of epithelial layer in vitro, distribution and expression of junction proteins both in vivo and in vitro were used to evaluate the epithelial barrier function. Western Blot was used to evaluate the expression of junction proteins and phosphorylated AKT in cells and lung tissues while ELISA were used to evaluate the Hsp90α expression and cytokines release in the lung homogenate. Results HDM resulted in a dysfunction of airway epithelial barrier both in vivo and in vitro, paralleled with the increased expression and release of Hsp90α. All of which were rescued in Hsp90α-knockdown cells or co-administration of 1G6-D7. Furthermore, either 1G6-D7 or PI3K inhibitor LY294002 suppressed the significant phosphorylation of AKT, which caused by secreted and recombinant Hsp90α, resulting in the restoration of epithelial barrier function. Conclusions Secreted Hsp90α medicates HDM-induced asthmatic airway epithelial barrier dysfunction via PI3K/AKT pathway, indicating that anti-secreted Hsp90α therapy might be a potential treatment to asthma in future.

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Titanium dioxide nanoparticles exacerbate pneumonia in respiratory syncytial virus (RSV)-infected mice

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2015.02.017 ◽

2015 ◽

Vol 39 (2) ◽

pp. 879-886 ◽

Cited By ~ 10

Author(s):

Seiko Hashiguchi ◽

Hiroki Yoshida ◽

Toshi Akashi ◽

Keiji Komemoto ◽

Tomoyuki Ueda ◽

...

Keyword(s):

Titanium Dioxide ◽

Respiratory Syncytial Virus ◽

Titanium Dioxide Nanoparticles ◽

Syncytial Virus

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Azithromycin prevents airway epithelial barrier dysfunction induced by sulphur dioxide inhalation

10.1183/13993003.congress-2020.4782 ◽

2020 ◽

Author(s):

Jennifer Kricker ◽

Thorarinn Gudjonsson ◽

Ari Jon Arason ◽

Jon Pétur Joelsson ◽

Bryndis Valdimarsdottir ◽

...

Keyword(s):

Sulphur Dioxide ◽

Epithelial Barrier ◽

Airway Epithelial ◽

Barrier Dysfunction ◽

Epithelial Barrier Dysfunction

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Titanium Dioxide Nanoparticles Modulate Respiratory Syncytial Virus Infection By Regulating Nerve Growth Factor In Bronchial Epithelial Cells

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a1021 ◽

2012 ◽

Author(s):

Sreeparna Chakraborty ◽

Sreekumar Othumpangat ◽

Lennie J. Samsell ◽

Cheryl Walton ◽

Vincent Castranova ◽

...

Keyword(s):

Titanium Dioxide ◽

Respiratory Syncytial Virus ◽

Nerve Growth Factor ◽

Growth Factor ◽

Epithelial Cells ◽

Virus Infection ◽

Respiratory Syncytial Virus Infection ◽

Titanium Dioxide Nanoparticles ◽

Bronchial Epithelial ◽

Syncytial Virus

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Effects of cigarette smoke on barrier function and tight junction proteins in the bronchial epithelium: protective role of cathelicidin LL-37

Respiratory Research ◽

10.1186/s12931-019-1226-4 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 11

Author(s):

Miyoko Tatsuta ◽

Keiko Kan-o ◽

Yumiko Ishii ◽

Norio Yamamoto ◽

Tomohiro Ogawa ◽

...

Keyword(s):

Protein Expression ◽

Cigarette Smoke ◽

Barrier Function ◽

Bronchial Epithelium ◽

Epithelial Barrier ◽

Airway Epithelial ◽

Barrier Dysfunction ◽

Expression Levels ◽

Gene And Protein Expression ◽

Epithelial Barrier Dysfunction

Abstract Background Airway epithelial barrier function is maintained by the formation of tight junctions (TJs) and adherens junctions (AJs). Inhalation of cigarette smoke causes airway epithelial barrier dysfunction and may contribute to the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). We assessed the effects of cigarette smoke on barrier function and expression of multiple TJ and AJ proteins in the bronchial epithelium. We also examined whether treatment with glucocorticosteroids (GCSs), long-acting β2-agonists (LABAs), and human cathelicidin LL-37 can protect against cigarette smoke extract (CSE)-induced barrier dysfunction. Methods Calu-3 cells cultured at the air-liquid interface were pretreated with or without GCSs, LABAs, GCSs plus LABAs, or LL-37, and subsequently exposed to CSE. Barrier function was assessed by transepithelial electronic resistance (TEER) measurements. Gene and protein expression levels of TJ and AJ proteins were analyzed by quantitative PCR and western blotting, respectively. Immunofluorescence staining of TJ and AJ proteins was performed. Results CSE decreased TEER and increased permeability in a concentration-dependent manner. CSE suppressed gene expression of claudin-1, claudin-3, claudin-4, claudin-7, claudin-15, occludin, E-cadherin, junctional adhesion molecule-A (JAM-A) and zonula occludens-1 (ZO-1) within 12 h post-CSE exposure, while suppressed protein expression levels of occludin at 12 h. CSE-treated cells exhibited discontinuous or attenuated immunostaining for claudin-1, claudin-3, claudin-4, occludin, ZO-1, and E-cadherin compared with untreated cells. GCS treatment partially restored CSE-induced TEER reduction, while LABA treatment had no effect. GCS and LABA combination treatment had no additive effect on CSE-induced TEER reduction and gene suppression of TJ and AJ proteins. Human cathelicidin LL-37 counteracted CSE-induced TEER reduction and prevented disruption of occludin and ZO-1. LL-37 also attenuated CSE-induced decreases in gene and protein expression levels of occludin. Conclusions CSE caused airway epithelial barrier dysfunction and simultaneously downregulated multiple TJ and AJ proteins. GCS and LABA combination treatment had no additive effect on CSE-induced TEER reduction. LL-37 counteracted CSE-induced TEER reduction and prevented disruption of occludin and ZO-1. Use of LL-37 to counteract airway epithelial barrier dysfunction may have significant benefits for respiratory diseases such as asthma and COPD.

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