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 Airway epithelial integrin β4 suppresses allergic inflammation by decreasing CCL17 production

2020 ◽  
Vol 134 (13) ◽  
pp. 1735-1749 ◽  
Author(s):  
Lin Yuan ◽  
Xun Zhang ◽  
Ming Yang ◽  
Xizi Du ◽  
Leyuan Wang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Allergic Inflammation ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Th2 Response ◽  
Integrin Β4 ◽  
Dust Mite ◽  
Asthma Patients ◽  
Deficient Mice

Abstract Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin β4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway epithelium of asthma patients. Although a few studies hint toward the role of ITGB4 in asthmatic inflammation pathogenesis, their specific resultant effects remain unexplored. In the present study, we determined the role of ITGB4 of AECs in the regulation of Th2 response and identified the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated lung inflammation and AHR with higher production of CCL17 in house dust mite (HDM)-treated mice. ITGB4 regulated CCL17 production in AECs through EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 both inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated the involvement of ITGB4 deficiency in the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway in AECs.

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

2019 ◽  
Vol 19 (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.

Protective effect of substance P on permeability of airway epithelial cells in culture

1996 ◽  
Vol 271 (6) ◽  
pp. L889-L895
Author(s):  
X. Y. Yu ◽  
B. J. Undem ◽  
E. W. Spannhake
Keyword(s):  
Substance P ◽  
Protective Effect ◽  
Barrier Function ◽  
Protective Role ◽  
Airway Epithelial Cells ◽  
Epithelial Barrier ◽  
Airway Epithelial ◽  
Bronchial Epithelial ◽  
Epithelial Barrier Function ◽  
Nk3 Receptor

Although substance P (SP) has been shown to mediate microvascular leakage in response to various stimuli, some data suggest that, in contrast, SP may play a protective role in the maintenance of airway epithelial integrity. To investigate the effect of SP on epithelial barrier function, we measured paracellular mannitol flux and the transepithelial potential difference (PD) of human bronchial epithelial (HBE) and canine bronchial epithelial (CBE) cells. Incubation of confluent cell cultures with SP had no effect on baseline flux. However, pretreatment inhibited the flux-enhancing effects of 0.5 ppm ozone by 50% in HBE cells and 40% in CBE cells and inhibited the ozone-induced decrease in PD in CBE cells by 54%. SP-afforded protection was reduced by the neurokinin (NK)-1 receptor antagonist CP-96,345.NK1 and NK3 receptor agonists also inhibited ozone-induced permeability, whereas an NK2 receptor agonist was without significant effect. These data indicate that SP exerts a protective effect on bronchial epithelial barrier function under conditions of challenge, which appears to be mediated in large part through NK1 receptors.

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 Secretoglobin Superfamily Protein SCGB3A2 Deficiency Potentiates Ovalbumin-Induced Allergic Pulmonary Inflammation

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Taketomo Kido ◽  
Mitsuhiro Yoneda ◽  
Yan Cai ◽  
Tsutomu Matsubara ◽  
Jerrold M. Ward ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Pulmonary Inflammation ◽  
Physiological Role ◽  
Secretory Protein ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Small Molecular Weight ◽  
Mixed Genetic Background ◽  
Anti Inflammatory

Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, which may play a role in lung inflammation, is predominantly expressed in airway epithelial cells. In order to understand the physiological role of SCGB3A2,Scgb3a2−/−mice were generated and characterized.Scgb3a2−/−mice did not exhibit any overt phenotypes. In ovalbumin- (OVA-) induced airway allergy inflammation model,Scgb3a2−/−mice in mixed background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenicScgb3a2−/−mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates. These results indicate that the loss of SCGB3A2 function was influenced by a modifier gene(s) in mixed genetic background and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent.

scholarly journals CDH26 amplifies airway epithelial IL-4 receptor α signaling in asthma

2020 ◽  
Author(s):  
Yuchen Feng ◽  
Shengchong Chen ◽  
Chenli Chang ◽  
Wenliang Wu ◽  
Dian Chen ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
Allergic Airway Disease ◽  
Airway Epithelial ◽  
Mucus Production ◽  
Bronchial Epithelial ◽  
Asthma Patients ◽  
Airway Mucus

ABSTRACTBackgroundActivation of interleukin (IL)-4 receptor (R) signaling in airway epithelial cells leads to airway hyperresponsiveness and mucus overproduction in asthma. Cadherin-26 (CDH26), a cadherin implicated in polarization of airway epithelial cells, is upregulated in asthma. However, the role of CDH26 in asthma remains unknown. We hypothesize that CDH26 plays a role in airway epithelial IL-4R signaling in asthma.MethodsWe measured airway resistance, mucus production, airway inflammation, and Il-4Rα expression in Cdh26-/- and WT mice after allergen sensitization and challenge. We explored the role of CDH26 in IL-4R signaling, mucin genes and eosinophilic chemokine expression in cultured bronchial epithelial cells and bronchial brushings from asthma patients.ResultsCdh26 deficiency nearly blocked airway mucus overproduction, and suppressed AHR and airway eosinophilia in a murine model of allergic airway disease. Interestingly, Il-4Rα expression in airway epithelium was markedly reduced in Cdh26-/- mice. In cultured human bronchial epithelial cells, CDH26 knockdown inhibited IL-13, a ligand for IL-4R, -induced IL-4Rα and IL-13Rα1 expression, and suppressed the downstream Jak1 and Stat6 phosphorylation. Moreover, CDH26 knockdown inhibited IL-13-induced MUC5AC, MUC5B and eosinophilic chemokines CCL11, CCL24, CCL26 expression. In contrast, CDH26 overexpression intensified IL-13-induced activation of IL-4Rα signaling. In asthma patients, CDH26 was the only one upregulated of 11 cadherins in bronchial brushings. CDH26 expression significantly correlated with epithelial IL-4Rα, MUC5AC expression, sputum eosinophilia and fractional exhaled nitric oxide (FeNO).ConclusionTaken together, CDH26 is an amplifier of epithelial IL-4R signaling in asthma, and may represent a therapeutic target for airway mucus overproduction.

scholarly journals Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ian T. Stancil ◽  
Jacob E. Michalski ◽  
Duncan Davis-Hall ◽  
Hong Wei Chu ◽  
Jin-Ah Park ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Airway Epithelium ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Chronic Lung Diseases ◽  
Distal Airway ◽  
Signaling Axis

AbstractThe airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

scholarly journals PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aubrey N. Michi ◽  
Bryan G. Yipp ◽  
Antoine Dufour ◽  
Fernando Lopes ◽  
David Proud
Keyword(s):  
Host Defense ◽  
Barrier Function ◽  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Cellular Damage ◽  
Epithelial Barrier ◽  
Airway Epithelial ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Function ◽  
Epithelial Damage

AbstractHuman rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. Although viral induced epithelial damage mediates inflammation, the molecular mechanisms responsible for airway epithelial damage and dysfunction remain undefined. Using experimental HRV infection studies in highly differentiated human bronchial epithelial cells grown at air-liquid interface (ALI), we examine the links between viral host defense, cellular metabolism, and epithelial barrier function. We observe that early HRV-C15 infection induces a transitory barrier-protective metabolic state characterized by glycolysis that ultimately becomes exhausted as the infection progresses and leads to cellular damage. Pharmacological promotion of glycolysis induces ROS-dependent upregulation of the mitochondrial metabolic regulator, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), thereby restoring epithelial barrier function, improving viral defense, and attenuating disease pathology. Therefore, PGC-1α regulates a metabolic pathway essential to host defense that can be therapeutically targeted to rescue airway epithelial barrier dysfunction and potentially prevent severe respiratory complications or secondary bacterial infections.

scholarly journals Eosinophil Responses at the Airway Epithelial Barrier during the Early Phase of Influenza a Virus Infection in C57BL/6 Mice

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 509 ◽  
Author(s):  
Meenakshi Tiwary ◽  
Robert J. Rooney ◽  
Swantje Liedmann ◽  
Kim S. LeMessurier ◽  
Amali E. Samarasinghe
Keyword(s):  
Epithelial Cells ◽  
Influenza A Virus ◽  
Early Phase ◽  
Influenza A ◽  
Airway Epithelial Cells ◽  
Epithelial Barrier ◽  
Virus Infectivity ◽  
Airway Epithelial ◽  
In Vivo Models

Eosinophils, previously considered terminally differentiated effector cells, have multifaceted functions in tissues. We previously found that allergic mice with eosinophil-rich inflammation were protected from severe influenza and discovered specialized antiviral effector functions for eosinophils including promoting cellular immunity during influenza. In this study, we hypothesized that eosinophil responses during the early phase of influenza contribute to host protection. Using in vitro and in vivo models, we found that eosinophils were rapidly and dynamically regulated upon influenza A virus (IAV) exposure to gain migratory capabilities to traffic to lymphoid organs after pulmonary infection. Eosinophils were capable of neutralizing virus upon contact and combinations of eosinophil granule proteins reduced virus infectivity through hemagglutinin inactivation. Bi-directional crosstalk between IAV-exposed epithelial cells and eosinophils occurred after IAV infection and cross-regulation promoted barrier responses to improve antiviral defenses in airway epithelial cells. Direct interactions between eosinophils and airway epithelial cells after IAV infection prevented virus-induced cytopathology in airway epithelial cells in vitro, and eosinophil recipient IAV-infected mice also maintained normal airway epithelial cell morphology. Our data suggest that eosinophils are important in the early phase of IAV infection providing immediate protection to the epithelial barrier until adaptive immune responses are deployed during influenza.

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