Hyaluronan and Layilin Mediate Loss of Airway Epithelial Barrier Function Induced by Cigarette Smoke by Decreasing E-cadherin

Forteza, Rosanna; Casalino‐Matsuda, S. Marina; Falcon, Nieves Santos; Gattas, Monica Valencia; Monzón, Maria E.

doi:10.1074/jbc.m112.387795

Cited by 71 publications

(76 citation statements)

References 79 publications

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“…Inhibition of Rho kinase reduced MLC phosphorylation, a target of the Rho/ROCK pathway, thus producing airway relaxation [51]. Cigarette smoke caused AJC disruption and increased epithelial permeability via triggering the RhoA/ROCK signaling pathway in bronchial epithelial cells [39]. In agreement with these findings, our study also found both HDM increased RhoA activity at 6 h and promoted MLC phosphorylation beginning 6 h, which remained elevated for many hours.…”

Section: Discussionsupporting

confidence: 84%

Extracellular heat shock protein 90α mediates HDM-induced bronchial epithelial barrier dysfunction by activating RhoA/MLC signaling

Dong

Wang

et al. 2017

Respir Res

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BackgroundThe disruption and hyperpermeability of bronchial epithelial barrier are closely related to the pathogenesis of asthma. House dust mite (HDM), one of the most important allergens, could increase the airway epithelial permeability. Heat shock protein (Hsp) 90α is also implicated in the lung endothelial barrier dysfunction by disrupting RhoA signaling. However, the effect of extracellular Hsp90α (eHsp90α) on the bronchial epithelial barrier disruption induced by HDM has never been reported.MethodsTo investigate the involvement of eHsp90α in the bronchial epithelial barrier disruption induced by HDM, normal human bronchial epithelial cell line 16HBE14o- (16HBE) cells were treated by HDM, human recombinant (hr) Hsp90α and hrHsp90β respectively and pretreated by1G6-D7, a specific anti-secreted Hsp90α monoclonal antibody (mAb). Hsp90α-silencing cells were also constructed. To further evaluate the role of RhoA signaling in this process, cells were pretreated by inhibitors of Rho kinase, GSK429286A and Y27632 2HCl. Transepithelial electrical resistance (TEER) and FITC-dextran flux (FITC-DX) were examined as the epithelial barrier function. Expression and localization of adherens junctional proteins E-cadherin and β-catenin were evaluated by western blotting and immunofluorescence respectively. The level of eHsp90α was investigated by concentration and purification of condition media. RhoA activity was determined by using a Rho G-LISA® RhoA activation assay kitTM biochem kit, and the phosphorylation of myosin light chain (MLC), the downstream signal molecule of RhoA, was assessed by western blotting.ResultsThe epithelial barrier disruption and the loss of adherens junctional proteins E-cadherin and β-catenin in cytomembrane were observed in HDM-treated 16HBE cells, paralleled with the increase of eHsp90α secretion. All of which were rescued in Hsp90α-silencing cells or by pretreating 16HBE cells with 1G6-D7. Also, 1G6-D7 suppressed RhoA activity and MLC phosphorylation induced by HDM. Furthermore, inhibitors of Rho kinase prevented and restored the airway barrier disruption. Consistently, it was hrHsp90α instead of hrHsp90β that promoted barrier dysfunction and activated RhoA/MLC signaling in 16HBE cells.ConclusionsThe eHsp90α mediates HDM-induced human bronchial epithelial barrier dysfunction by activating RhoA/MLC signaling, suggesting that eHsp90α is a potential therapeutic target for treatment of asthma.

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Section: Discussionsupporting

confidence: 84%

Extracellular heat shock protein 90α mediates HDM-induced bronchial epithelial barrier dysfunction by activating RhoA/MLC signaling

Dong

Wang

et al. 2017

Respir Res

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“…In addition to the classic tight‐junction proteins claudins, occludins, and zonula occludens (ZOs), the adherens junction protein E‐cadherin also plays a pivotal role in tight‐junction development and maintenance. The absence or downregulation of E‐cadherin leads to the improper formation of tight junctions, resulting in permeability increase and dysfunction of epithelium barriers . Downregulation of E‐cadherin in BPH specimens was observed by our group and others .…”

Section: Introductionsupporting

confidence: 56%

E‐cadherin is downregulated in benign prostatic hyperplasia and required for tight junction formation and permeability barrier in the prostatic epithelial cell monolayer

Pascal

Stolz

et al. 2019

The Prostate

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Background We previously reported the presence of prostate‐specific antigen (PSA) in the stromal compartment of benign prostatic hyperplasia (BPH). Since PSA is expressed exclusively by prostatic luminal epithelial cells, PSA in the BPH stroma suggests increased tissue permeability and the compromise of epithelial barrier integrity. E‐cadherin, an important adherens junction component and tight junction regulator, is known to exhibit downregulation in BPH. These observations suggest that the prostate epithelial barrier is disrupted in BPH and E‐cadherin downregulation may increase epithelial barrier permeability. Methods The ultra‐structure of cellular junctions in BPH specimens was observed using transmission electron microscopy (TEM) and E‐cadherin immunostaining analysis was performed on BPH and normal adjacent specimens from BPH patients. In vitro cell line studies using benign prostatic epithelial cell lines were performed to determine the impact of small interfering RNA knockdown of E‐cadherin on transepithelial electrical resistance and diffusion of fluorescein isothiocyanate (FITC)‐dextran in transwell assays. Results The number of kiss points in tight junctions was reduced in BPH epithelial cells as compared with the normal adjacent prostate. Immunostaining confirmed E‐cadherin downregulation and revealed a discontinuous E‐cadherin staining pattern in BPH specimens. E‐cadherin knockdown increased monolayer permeability and disrupted tight junction formation without affecting cell density. Conclusions Our results indicate that tight junctions are compromised in BPH and loss of E‐cadherin is potentially an important underlying mechanism, suggesting targeting E‐cadherin loss could be a potential approach to prevent or treat BPH.

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“…Options include direct secretion from the airway epithelium, airway smooth muscle cells, goblet cells, mucus glands, or a combination of these. Among these options, the direct secretion from the airway epithelium and airways smooth muscle cells are the most likely, and several studies have demonstrated the ability of the epithelium and airways smooth muscle cells to secrete HA in vitro (3,37,38). The relatively negative staining of HA in goblet cell and mucous gland cell populations indicates that these cells are less likely to be involved in the secretion of HA into the airway lumen.…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan and Its Heavy Chain Modification in Asthma Severity and Experimental Asthma Exacerbation

Lauer

Majors

Comhair

et al. 2015

Journal of Biological Chemistry

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Background: Hyaluronan has been linked to asthma severity and inflammation. Results: We characterized the hyaluronan levels and its heavy chain modification in an experimental model of human asthma exacerbation. Conclusion: These data implicate hyaluronan and its heavy chain modification in human asthma severity. Significance: Repetitive asthma exacerbations exacerbate hyaluronan pathobiology, which contribute to the chronic inflammation associated with this disease.

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Hyaluronan and Layilin Mediate Loss of Airway Epithelial Barrier Function Induced by Cigarette Smoke by Decreasing E-cadherin

Cited by 71 publications

References 79 publications

Extracellular heat shock protein 90α mediates HDM-induced bronchial epithelial barrier dysfunction by activating RhoA/MLC signaling

Extracellular heat shock protein 90α mediates HDM-induced bronchial epithelial barrier dysfunction by activating RhoA/MLC signaling

E‐cadherin is downregulated in benign prostatic hyperplasia and required for tight junction formation and permeability barrier in the prostatic epithelial cell monolayer

Hyaluronan and Its Heavy Chain Modification in Asthma Severity and Experimental Asthma Exacerbation

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