Loss of E-cadherin is causal to pathologic changes in chronic lung disease

Ghosh, Baishakhi; Loube, Jeffrey; Thapa, Shreeti; Ryan, Hurley; Capodanno, Erin; Chen, Daniel; Swaby, Carter; Chen, Si; Mahmud, Saborny; Girgis, Mirit; Nishida, Kristine; Ying, Linyan; Chengala, Pratulya Pragadaraju; Tieng, Ethan; Burnim, Michael; Wally, Ara; Bhowmik, Debaleena; Zaykaner, Michael; Yeung-Luk, Bonnie; Mitzner, Wayne; Biswal, Shyam; Sidhaye, Venkataramana K.

doi:10.1038/s42003-022-04150-w

Cited by 16 publications

(28 citation statements)

References 47 publications

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“…E-cadherin is a transmembrane glycoprotein which presents on the lateral surfaces of epithelial cells and functions as a cell adhesion [ 24 ]. Loss of E-cadherin is associated with lung diseases such as asthma and chronic obstructive pulmonary disease [ 25 ]. HIF-1α signaling pathway may play a key role in the development of ALI.…”

Section: Introductionmentioning

confidence: 99%

Protective effects of pentoxifylline against chlorine-induced acute lung injury in rats

Liu

Zhao

et al. 2023

BMC Pharmacol Toxicol

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Objective Chlorine is a chemical threat agent that can be harmful to humans. Inhalation of high levels of chlorine can lead to acute lung injury (ALI). Currently, there is no satisfactory treatment, and effective antidote is urgently needed. Pentoxifylline (PTX), a methylxanthine derivative and nonspecific phosphodiesterase inhibitor, is widely used for the treatment of vascular disorders. The present study was aimed to investigate the inhibitory effects of PTX on chlorine-induced ALI in rats. Methods Adult male Sprague-Dawley rats were exposed to 400 ppm Cl2 for 5 min. The histopathological examination was carried out and intracellular reactive oxygen species (ROS) levels were measured by the confocal laser scanning system. Subsequently, to evaluate the effect of PTX, a dose of 100 mg/kg was administered. The activities of superoxide dismutase (SOD) and the contents of malondialdehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG) and lactate dehydrogenase (LDH) were determined by using commercial kits according to the manufacturer’s instructions. Western blot assay was used to detect the protein expressions of SOD1, SOD2, catalase (CAT), hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), occludin, E-cadherin, bcl-xl, LC 3, Beclin 1, PTEN-induced putative kinase 1 (PINK 1) and Parkin. Results The histopathological examination demonstrated that chlorine could destroy the lung structure with hemorrhage, alveolar collapse, and inflammatory infiltration. ROS accumulation was significantly higher in the lungs of rats suffering from inhaling chlorine (P<0.05). PTX markedly reduced concentrations of MAD and GSSG, while increased GSH (P<0.05). The protein expression levels of SOD1 and CAT also decreased (P<0.05). Furthermore, the activity of LDH in rats treated with PTX was significantly decreased compared to those of non-treated group (P<0.05). Additionally, the results also showed that PTX exerted an inhibition effect on protein expressions of HIF-1α, VEGF and occludin, and increased the level of E-cadherin (P<0.05). While the up-regulation of Beclin 1, LC 3II/I, Bcl-xl, and Parkin both in the lung tissues and mitochondria, were found in PTX treated rats (P<0.05). The other protein levels were decreased when treated with PTX (P<0.05). Conclusion PTX could ameliorate chlorine-induced lung injury via inhibition effects on oxidative stress, hypoxia and autophagy, thus suggesting that PTX could serve as a potential therapeutic approach for ALI.

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Section: Introductionmentioning

confidence: 99%

Protective effects of pentoxifylline against chlorine-induced acute lung injury in rats

Liu

Zhao

et al. 2023

BMC Pharmacol Toxicol

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“…25 Diseased COPD epithelium demonstrates decreased apical junctional proteins (ZO-1 (TJP1), OCLN, E-cadherin) compared with normal bronchial epithelium. 15,26,27 Notably, when the apical-adherens junction protein, E-cadherin, is not expressed in the epidermis, the tight junction proteins ZO-1 (TJP1), occludin, and claudins are also not properly formed, leading to reduced epithelial resistance in bronchial epithelial cells. 28 IPF patients have also been shown to have reduced protein expression of E-cadherin leading to increased alveolar permeability and subsequent chronic inflammation and fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Antigen penetrance through a dysfunctional epithelial barrier is a common pathologic phenotype driving other fibroinflammatory airway diseases such as IPF and COPD 25 . Diseased COPD epithelium demonstrates decreased apical junctional proteins (ZO‐1 (TJP1), OCLN, E‐cadherin) compared with normal bronchial epithelium 15,26,27 . Notably, when the apical‐adherens junction protein, E‐cadherin, is not expressed in the epidermis, the tight junction proteins ZO‐1 (TJP1), occludin, and claudins are also not properly formed, leading to reduced epithelial resistance in bronchial epithelial cells 28 .…”

Section: Discussionmentioning

confidence: 99%

“…A MATLAB (R2018b) script (validated against SAVA) was used to determine the average CBF per video, to generate a heat map indicating CBF, and to determine percent pixels moving and cilia coverage. 14,15,19,21 Average Growth Rate Growth rate was assessed during a 2-week period of differentiation. Scar and normal epithelial cells were sampled and manually counted using hemocytometer at three different time points day 0, day 7, and day 14.…”

Section: Cbf and Cilia Coveragementioning

confidence: 99%

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Dysfunctional Epithelial Barrier Is Characterized by Reduced E‐Cadherin in Idiopathic Subglottic Stenosis

Berges¹,

Ospino

Mafla

et al. 2023

The Laryngoscope

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ObjectivesTo aim of the study was to characterize the molecular profile and functional phenotype of idiopathic subglottic stenosis (iSGS)‐scar epithelium.MethodsHuman tracheal biopsies from iSGS scar (n = 6) and matched non‐scar (n = 6) regions were analyzed using single‐cell RNA sequencing (scRNA‐seq). Separate specimens were used for epithelial cell expansion in vitro to assess average growth rate and functional capabilities using transepithelial‐electrical resistance (TEER), fluorescein isothiocyanate‐dextran flux permeability assay, ciliary coverage, and cilia beating frequency (CBF). Finally, epithelial tight junction protein expression of cultured cells was quantified using immunoblot assay (n = 4) and immunofluorescence (n = 6).ResultsscRNA‐seq analysis revealed a decrease in goblet, ciliated, and basal epithelial cells in the scar iSGS cohort. Furthermore, mRNA expression of proteins E‐cadherin, claudin‐3, claudin‐10, occludin, TJP1, and TJP2 was also reduced (p < 0.001) in scar epithelium. Functional assays demonstrated a decrease in TEER (paired 95% confidence interval [CI], 195.68–890.83 Ω × cm2, p < 0.05), an increase in permeability (paired 95% CI, −6116.00 to −1401.99 RFU, p < 0.05), and reduced epithelial coverage (paired 95% CI, 0.1814–1.766, fold change p < 0.05) in iSGS‐scar epithelium relative to normal controls. No difference in growth rate (p < 0.05) or CBF was found (paired 95% CI, −2.118 to 3.820 Hz, p > 0.05). Immunoblot assay (paired 95% CI, 0.0367–0.605, p < 0.05) and immunofluorescence (paired 95% CI, 13.748–59.191 mean grey value, p < 0.05) revealed E‐cadherin reduction in iSGS‐scar epithelium.ConclusioniSGS‐scar epithelium has a dysfunctional barrier and reduced structural protein expression. These results are consistent with dysfunctional epithelium seen in other airway pathology. Further studies are warranted to delineate the causality of epithelial dysfunction on the downstream fibroinflammatory cascade in iSGS.Level of EvidenceNA Laryngoscope, 2023

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“…Our lab has demonstrated that primary bronchial epithelial cells derived from patients with COPD have a significant reduction in E-cadherin levels compared to age- and sex-matched normal cells (15, 16). Moreover, we have found that loss of E-cadherin can drive epithelial dysfunction and tissue remodeling (15) in mouse models. However, mechanisms of modulating E-cadherin in COPD are unknown.…”

Section: Introductionmentioning

confidence: 97%

Decreased fucosylation impacts epithelial integrity and increases risk for COPD

Swaby,

Yeung-Luk,

Thapa

et al. 2023

Preprint

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COPD causes significant morbidity and mortality worldwide. Epithelial damage is fundamental to disease pathogenesis, although the mechanisms driving disease remain undefined. Published evidence from a COPD cohort (SPIROMICS) and confirmed in a second cohort (COPDgene) demonstrate a polymorphism inFucosyltransferese-2 (FUT2)is a trans-pQTL for E-cadherin, which is critical in COPD pathogenesis. We found by MALDI-TOF analysis thatFUT2increased terminal fucosylation of E-cadherin. Using atomic force microscopy, we found that FUT2-dependent fucosylation enhanced E-cadherin-E-cadherin bond strength, mediating the improvement in monolayer integrity. Tracheal epithelial cells fromFut2-/-mice have reduced epithelial integrity, which is recovered with reconstitution ofFut2. Overexpression ofFUT2in COPD derived epithelia rescues barrier function.Fut2-/-mice show increased susceptibility in an elastase model of disease developing both emphysema and fibrosis. We propose this is due to the role ofFUT2in proliferation and cell differentiation. Overexpression of FUT2 significantly increased proliferation. Loss ofFut2results in accumulation of Spc+ cells suggesting a failure of alveolar type 2 cells to undergo transdifferentiation to alveolar type 1. Using a combination of population data, genetically manipulated mouse models, and patient-derived cells, we present a novel mechanism by which post-translational modifications modulate tissue pathology and serve as a proof of concept for the development of a disease-modifying target in COPD.

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Loss of E-cadherin is causal to pathologic changes in chronic lung disease

Cited by 16 publications

References 47 publications

Protective effects of pentoxifylline against chlorine-induced acute lung injury in rats

Protective effects of pentoxifylline against chlorine-induced acute lung injury in rats

Dysfunctional Epithelial Barrier Is Characterized by Reduced E‐Cadherin in Idiopathic Subglottic Stenosis

Decreased fucosylation impacts epithelial integrity and increases risk for COPD

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