scholarly journals The Significance of Hypothiocyanite Production via the Pendrin/DUOX/Peroxidase Pathway in the Pathogenesis of Asthma

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Kenji Izuhara ◽  
Shoichi Suzuki ◽  
Masahiro Ogawa ◽  
Satoshi Nunomura ◽  
Yasuhiro Nanri ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Inhaled Corticosteroids ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Apical Side ◽  
Asthma Patients ◽  
High Doses ◽  
Antithyroid Agents ◽  
Antiasthma Drugs

Inhaled corticosteroids (ICSs) are used as first-line drugs for asthma, and various novel antiasthma drugs targeting type 2 immune mediators are now under development. However, molecularly targeted drugs are expensive, creating an economic burden on patients. We and others previously found pendrin/SLC26A4 as a downstream molecule of IL-13, a signature type 2 cytokine critical for asthma, and showed its significance in the pathogenesis of asthma using model mice. However, the molecular mechanism of how pendrin causes airway inflammation remained elusive. We have recently demonstrated that hypothiocyanite (OSCN−) produced by the pendrin/DUOX/peroxidase pathway has the potential to cause airway inflammation. Pendrin transports thiocyanate (SCN−) into pulmonary lumens at the apical side. Peroxidases catalyze SCN− and H2O2 generated by DUOX into OSCN−. Low doses of OSCN− activate NF-κB in airway epithelial cells, whereas OSCN− in high doses causes necrosis of the cells, inducing the release of IL-33 and accelerating inflammation. OSCN− production is augmented in asthma model mice and possibly in some asthma patients. Heme peroxidase inhibitors, widely used as antithyroid agents, diminish asthma-like phenotypes in mice, indicating the significance of this pathway. These findings suggest the possibility of repositioning antithyroid agents as antiasthma drugs.

scholarly journals Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Charu Rajput ◽  
Mingyuan Han ◽  
Tomoko Ishikawa ◽  
Jing Lei ◽  
Adam M. Goldsmith ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Airway Inflammation ◽  
Airway Epithelial Cells ◽  
Lymphoid Cells ◽  
Airway Epithelial ◽  
Eosinophilic Inflammation ◽  
Asthma Exacerbations ◽  
Rhinovirus C ◽  
Type 2 Inflammation

Rhinovirus C (RV-C) infection is associated with severe asthma exacerbations. Since type 2 inflammation is an important disease mechanism in asthma, we hypothesized that RV-C infection, in contrast to RV-A, preferentially stimulates type 2 inflammation, leading to exacerbated eosinophilic inflammation. To test this, we developed a mouse model of RV-C15 airways disease. RV-C15 was generated from the full-length cDNA clone and grown in HeLa-E8 cells expressing human CDHR3. BALB/c mice were inoculated intranasally with 5 x 106 ePFU RV-C15, RV-A1B or sham. Mice inoculated with RV-C15 showed lung viral titers of 1 x 105 TCID50 units 24 h after infection, with levels declining thereafter. IFN-α, β, γ and λ2 mRNAs peaked 24-72 hrs post-infection. Immunofluorescence verified colocalization of RV-C15, CDHR3 and acetyl-α-tubulin in mouse ciliated airway epithelial cells. Compared to RV-A1B, mice infected with RV-C15 demonstrated higher bronchoalveolar eosinophils, mRNA expression of IL-5, IL-13, IL-25, Muc5ac and Gob5/Clca, protein production of IL-5, IL-13, IL-25, IL-33 and TSLP, and expansion of type 2 innate lymphoid cells. Analogous results were found in mice treated with house dust mite before infection, including increased airway responsiveness. In contrast to Rorafl/fl littermates, RV-C-infected Rorafl/flIl7rcre mice deficient in ILC2s failed to show eosinophilic inflammation or mRNA expression of IL-13, Muc5ac and Muc5b. We conclude that, compared to RV-A1B, RV-C15 infection induces ILC2-dependent type 2 airway inflammation, providing insight into the mechanism of RV-C-induced asthma exacerbations.

Cross-reactive antibodies against dust mite-derived enolase induce neutrophilic airway inflammation

2020 ◽  
pp. 1902375 ◽  
Author(s):  
Jianli Lin ◽  
Nana Huang ◽  
Jing Li ◽  
Xiaoyu Liu ◽  
Qing Xiong ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Common Factor ◽  
Airway Epithelial Cells ◽  
Epithelial Barrier ◽  
Airway Epithelial ◽  
Epithelial Barrier Function ◽  
Neutrophilic Inflammation ◽  
Dust Mite ◽  
Asthma Patients

Background and aimsNeutrophilic inflammation is a hallmark of some specific asthma phenotypes; its etiology is not fully understood yet. House dust mite (HDM) is the most common factor involving with the pathogenesis of airway inflammation. This study aims to elucidate the role of cross-antibodies against HDM-derived factors in the development of neutrophilic inflammation in the airway.MethodsBlood samples were collected from asthma patients with chronic neutrophilic asthma to be analysed the HDM-specific cross-reactive antibodies. The role of an antibody against HDM-derived enolase (EnoAb) in the impairment of airway epithelial barrier function and induction of airway inflammation was assessed in a cell culture model and an animal model.ResultsHigh similarity (72%) of the enolase gene sequences was identified between HDM and human. Serum EnoAb was detected in patients with chronic neutrophilic asthma. The EnoAb bound to airway epithelial cells to form complexes with enolase, which activated complements, impaired airway epithelial barrier functions and induced neutrophilic inflammation in the airway tissues.ConclusionsHDM-derived enolase can induce specific cross-antibodies by human, which induce neutrophilic inflammation in the airway.

scholarly journals Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma

2021 ◽  
Vol 22 (9) ◽  
pp. 4369
Author(s):  
Corrado Pelaia ◽  
Giulia Pelaia ◽  
Claudia Crimi ◽  
Angelantonio Maglio ◽  
Luca Gallelli ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Human Monoclonal Antibody ◽  
Airway Epithelial Cells ◽  
Lymphoid Cells ◽  
Airway Epithelial ◽  
Airborne Pollutants ◽  
Group 2 ◽  
Efficacy Profile ◽  
Refractory Asthma

Thymic stromal lymphopoietin (TSLP) is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in asthma by acting as an upstream activator of cellular and molecular pathways leading to type 2 (T2-high) airway inflammation. Released from airway epithelial cells upon tissue damage induced by several noxious agents including allergens, viruses, bacteria, and airborne pollutants, TSLP activates dendritic cells and group 2 innate lymphoid cells involved in the pathobiology of T2-high asthma. Tezepelumab is a fully human monoclonal antibody that binds to TSLP, thereby preventing its interaction with the TSLP receptor complex. Preliminary results of randomized clinical trials suggest that tezepelumab is characterized by a good safety and efficacy profile in patients with severe, uncontrolled asthma.

scholarly journals Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation

Cell Research ◽  
2008 ◽  
Vol 18 (6) ◽  
pp. 649-663 ◽  
Author(s):  
Jing Wu ◽  
Rongqi Duan ◽  
Huibi Cao ◽  
Deborah Field ◽  
Catherine M Newnham ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Inflammation ◽  
Airway Epithelial Cells ◽  
Airway Epithelial

Decreased expression of uteroglobin-related protein 1 in inflamed mouse airways is mediated by IL-9

2004 ◽  
Vol 287 (6) ◽  
pp. L1193-L1198 ◽  
Author(s):  
Yoshihiko Chiba ◽  
Takashi Kusakabe ◽  
Shioko Kimura
Keyword(s):  
Epithelial Cells ◽  
Airway Inflammation ◽  
Inverse Correlation ◽  
Immunohistochemical Analysis ◽  
Secretory Protein ◽  
Airway Epithelial Cells ◽  
Mrna Levels ◽  
Airway Epithelial ◽  
Related Protein ◽  
Interleukin 9

Uteroglobin-related protein 1 (UGRP1) is a secretory protein, highly expressed in epithelial cells of airways. Although an involvement of UGRP1 in the pathogenesis of asthma has been suggested, its function in airways remains unclear. In the present study, a relationship between airway inflammation, UGRP1 expression, and interleukin-9 (IL-9), an asthma candidate gene, was evaluated by using a murine model of allergic bronchial asthma. A severe airway inflammation accompanied by airway eosinophilia and elevation of IL-9 in bronchoalveolar lavage (BAL) fluids was observed after ovalbumin (OVA) challenge to OVA-sensitized mice. In this animal model of airway inflammation, lung Ugrp1 mRNA expression was greatly decreased compared with control mice. A significant inverse correlation between lung Ugrp1 mRNA levels and IL-9 levels in BAL fluid was demonstrated by regression analysis ( r = 0.616, P = 0.023). Immunohistochemical analysis revealed a distinct localization of UGRP1 in airway epithelial cells of control mice, whereas UGRP1 staining was patchy and faint in inflamed airways. Intranasal administration of IL-9 to naive mice decreased the level of Ugrp1 expression in lungs. These findings suggest that UGRP1 is downregulated in inflamed airways, such as allergic asthmatics, and IL-9 might be an important mediator for modulating UGRP1 expression.

scholarly journals Cyclodextrins reduce the ability of Pseudomonas aeruginosa outer-membrane vesicles to reduce CFTR Cl− secretion

2019 ◽  
Vol 316 (1) ◽  
pp. L206-L215 ◽  
Author(s):  
Roxanna Barnaby ◽  
Katja Koeppen ◽  
Bruce A. Stanton
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Outer Membrane ◽  
Membrane Vesicles ◽  
Airway Epithelial Cells ◽  
Outer Membrane Vesicles ◽  
Airway Epithelial ◽  
Ussing Chambers ◽  
Planktonic Growth ◽  
Apical Side

Pseudomonas aeruginosa secretes outer-membrane vesicles (OMVs) that fuse with cholesterol-rich lipid rafts in the apical membrane of airway epithelial cells and decrease wt-CFTR Cl− secretion. Herein, we tested the hypothesis that a reduction of the cholesterol content of CF human airway epithelial cells by cyclodextrins reduces the inhibitory effect of OMVs on VX-809 (lumacaftor)-stimulated Phe508del CFTR Cl− secretion. Primary CF bronchial epithelial cells and CFBE cells were treated with vehicle, hydroxypropyl-β-cyclodextrin (HPβCD), or methyl-β-cyclodextrin (MβCD), and the effects of OMVs secreted by P. aeruginosa on VX-809 stimulated Phe508del CFTR Cl− secretion were measured in Ussing chambers. Neither HPβCD nor MβCD were cytotoxic, and neither altered Phe508del CFTR Cl− secretion. Both cyclodextrins reduced OMV inhibition of VX-809-stimulated Phe508del-CFTR Cl− secretion when added to the apical side of CF monolayers. Both cyclodextrins also reduced the ability of P. aeruginosa to form biofilms and suppressed planktonic growth of P. aeruginosa. Our data suggest that HPβCD, which is in clinical trials for Niemann-Pick Type C disease, and MβCD, which has been approved by the U.S. Food and Drug Administration for use in solubilizing lipophilic drugs, may enhance the clinical efficacy of VX-809 in CF patients when added to the apical side of airway epithelial cells, and reduce planktonic growth and biofilm formation by P. aeruginosa. Both effects would be beneficial to CF patients.

scholarly journals Virus Infection-Induced Bronchial Asthma Exacerbation

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Mutsuo Yamaya
Keyword(s):  
Epithelial Cells ◽  
Viral Infection ◽  
Airway Inflammation ◽  
Bronchial Asthma ◽  
Inflammatory Mediators ◽  
Asthma Exacerbation ◽  
Viral Infections ◽  
Inflammatory Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial

Infection with respiratory viruses, including rhinoviruses, influenza virus, and respiratory syncytial virus, exacerbates asthma, which is associated with processes such as airway inflammation, airway hyperresponsiveness, and mucus hypersecretion. In patients with viral infections and with infection-induced asthma exacerbation, inflammatory mediators and substances, including interleukins (ILs), leukotrienes and histamine, have been identified in the airway secretions, serum, plasma, and urine. Viral infections induce an accumulation of inflammatory cells in the airway mucosa and submucosa, including neutrophils, lymphocytes and eosinophils. Viral infections also enhance the production of inflammatory mediators and substances in airway epithelial cells, mast cells, and other inflammatory cells, such as IL-1, IL-6, IL-8, GM-CSF, RANTES, histamine, and intercellular adhesion molecule-1. Viral infections affect the barrier function of the airway epithelial cells and vascular endothelial cells. Recent reports have demonstrated augmented viral production mediated by an impaired interferon response in the airway epithelial cells of asthma patients. Several drugs used for the treatment of bronchial asthma reduce viral and pro-inflammatory cytokine release from airway epithelial cells infected with viruses. Here, I review the literature on the pathogenesis of the viral infection-induced exacerbation of asthma and on the modulation of viral infection-induced airway inflammation.

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