scholarly journals miR-146a-5p plays an essential role in the aberrant epithelial–fibroblast cross-talk in COPD

2017 ◽  
Vol 49 (5) ◽  
pp. 1602538 ◽  
Author(s):  
Emmanuel T. Osei ◽  
Laura Florez-Sampedro ◽  
Hataitip Tasena ◽  
Alen Faiz ◽  
Jacobien A. Noordhoek ◽  
...  
Keyword(s):  
Airway Epithelial Cells ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Single Nucleotide ◽  
Obstructive Pulmonary Disease ◽  
Bronchial Epithelial ◽  
Lung Epithelial ◽  
Inflammatory Phenotype

We previously reported that epithelial-derived interleukin (IL)-1α drives fibroblast-derived inflammation in the lung epithelial–mesenchymal trophic unit. Since miR-146a-5p has been shown to negatively regulate IL-1 signalling, we investigated the role of miR-146a-5p in the regulation of IL-1α-driven inflammation in chronic obstructive pulmonary disease (COPD).Human bronchial epithelial (16HBE14o-) cells were co-cultured with control and COPD-derived primary human lung fibroblasts (PHLFs), and miR-146a-5p expression was assessed with and without IL-1α neutralising antibody. Genomic DNA was assessed for the presence of the single nucleotide polymorphism (SNP) rs2910164. miR-146a-5p mimics were used for overexpression studies to assess IL-1α-induced signalling and IL-8 production by PHLFs.Co-culture of PHLFs with airway epithelial cells significantly increased the expression of miR-146a-5p and this induction was dependent on epithelial-derived IL-1α. miR-146a-5p overexpression decreased IL-1α-induced IL-8 secretion in PHLFs via downregulation of IL-1 receptor-associated kinase-1. In COPD PHLFs, the induction of miR-146a-5p was significantly less compared with controls and was associated with the SNP rs2910164 (GG allele) in the miR-146a-5p gene.Our results suggest that induction of miR-146a-5p is involved in epithelial–fibroblast communication in the lungs and negatively regulates epithelial-derived IL-1α induction of IL-8 by fibroblasts. The decreased levels of miR-146a-5p in COPD fibroblasts may induce a more pro-inflammatory phenotype, contributing to chronic inflammation in COPD.

Cigarette smoke irreversibly modifies glutathione in airway epithelial cells

2007 ◽  
Vol 293 (5) ◽  
pp. L1156-L1162 ◽  
Author(s):  
Marco van der Toorn ◽  
Maria P. Smit-de Vries ◽  
Dirk-Jan Slebos ◽  
Harold G. de Bruin ◽  
Nicolas Abello ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
A549 Cells ◽  
Airway Epithelial Cells ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Obstructive Pulmonary Disease ◽  
Bronchial Epithelial ◽  
Gsh Metabolism ◽  
Primary Bronchial Epithelial Cells

In patients with chronic obstructive pulmonary disease (COPD), an imbalance between oxidants and antioxidants is acknowledged to result in disease development and progression. Cigarette smoke (CS) is known to deplete total glutathione (GSH + GSSG) in the airways. We hypothesized that components in the gaseous phase of CS may irreversibly react with GSH to form GSH derivatives that cannot be reduced (GSX), thereby causing this depletion. To understand this phenomenon, we investigated the effect of CS on GSH metabolism and identified the actual GSX compounds. CS and H2O2 (control) deplete reduced GSH in solution [Δ = −54.1 ± 1.7 μM ( P < 0.01) and −39.8 ± 0.9 μM ( P < 0.01), respectively]. However, a significant decrease of GSH + GSSG was observed after CS (Δ = −75.1 ± 7.6 μM, P < 0.01), but not after H2O2. Exposure of A549 cells and primary bronchial epithelial cells to CS decreased free sulfhydryl (-SH) groups (Δ = −64.2 ± 14.6 μM/mg protein, P < 0.05) and irreversibly modified GSH + GSSG (Δ = −17.7 ± 1.9 μM, P < 0.01) compared with nonexposed cells or H2O2 control. Mass spectrometry (MS) showed that GSH was modified to glutathione-aldehyde derivatives. Further MS identification showed that GSH was bound to acrolein and crotonaldehyde and another, yet to be identified, structure. Our data show that CS does not oxidize GSH to GSSG but, rather, reacts to nonreducible glutathione-aldehyde derivatives, thereby depleting the total available GSH pool.

scholarly journals Airwayβ-Defensin-1 Protein Is Elevated in COPD and Severe Asthma

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Katherine J. Baines ◽  
Thomas K. Wright ◽  
Jodie L. Simpson ◽  
Vanessa M. McDonald ◽  
Lisa G. Wood ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Chronic Obstructive ◽  
Healthy Controls ◽  
Obstructive Pulmonary Disease ◽  
Bronchial Epithelial ◽  
Receiver Operating Characteristic Curves ◽  
Asthma Patients ◽  
Inflammatory Phenotype ◽  
Primary Bronchial Epithelial Cells

Background. Innate immune antimicrobial peptides, includingβ-defensin-1, promote the chemotaxis and activation of several immune cells. The role ofβ-defensin-1 in asthma and chronic obstructive pulmonary disease (COPD) remains unclear.Methods. Induced sputum was collected from healthy controls and individuals with asthma or COPD.β-defensin-1 protein in sputum supernatant was quantified by ELISA. Biomarker potential was examined using receiver operating characteristic curves.β-defensin-1 release from primary bronchial epithelial cells (pBECs) was investigated in culture with and without cigarette smoke extract (CSE).Results. Airwayβ-defensin-1 protein was elevated in COPD participants compared to asthma participants and healthy controls. Inflammatory phenotype had no effect onβ-defensin-1 levels in asthma or COPD.β-defensin-1 protein was significantly higher in severe asthma compared to controlled and uncontrolled asthma.β-defensin-1 protein could predict the presence of COPD from both healthy controls and asthma patients. Exposure of pBECs to CSE decreasedβ-defensin-1 production in healthy controls; however in pBECs from COPD participants the level ofβ-defensin-1 remanied unchanged.Conclusions. Elevatedβ-defensin-1 protein is a feature of COPD and severe asthma regardless of inflammatory phenotype.β-defensin-1 production is dysregulated in the epithelium of patients with COPD and may be an effective biomarker and potential therapeutic target.

scholarly journals The role of noncoding RNAs in regulating epithelial responses in COPD

2018 ◽  
Vol 315 (2) ◽  
pp. L184-L192 ◽  
Author(s):  
Yifan Chen ◽  
Paul S. Thomas ◽  
Rakesh K. Kumar ◽  
Cristan Herbert
Keyword(s):  
Inflammatory Responses ◽  
Noncoding Rnas ◽  
Chronic Inflammatory Disease ◽  
Airway Epithelial Cells ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Obstructive Pulmonary Disease ◽  
Regulatory Effects

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death in the world, is a chronic inflammatory disease of the airways usually caused by long-term exposure to inhaled irritants. Airway epithelial cells (AECs) play a key role in initializing COPD and driving the exacerbation of this disease through the release of various cytokines. This AEC-derived cytokine response is tightly regulated possibly through the regulatory effects of noncoding RNAs (ncRNAs). Although the importance of ncRNAs in pulmonary diseases has been increasingly realized, little is known about the role of ncRNA in the regulation of inflammatory responses in COPD. This review outlines the features of AEC-derived cytokine responses in COPD and how ncRNAs regulate these inflammatory responses.

scholarly journals Interleukin-1α drives the dysfunctional cross-talk of the airway epithelium and lung fibroblasts in COPD

2016 ◽  
Vol 48 (2) ◽  
pp. 359-369 ◽  
Author(s):  
Emmanuel T. Osei ◽  
Jacobien A. Noordhoek ◽  
Tillie L. Hackett ◽  
Anita I.R. Spanjer ◽  
Dirkje S. Postma ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Airway Epithelium ◽  
Fetal Lung ◽  
Bronchial Epithelial Cell ◽  
Airway Epithelial Cells ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
And Control

Chronic obstructive pulmonary disease (COPD) has been associated with aberrant epithelial–mesenchymal interactions resulting in inflammatory and remodelling processes. We developed a co-culture model using COPD and control-derived airway epithelial cells (AECs) and lung fibroblasts to understand the mediators that are involved in remodelling and inflammation in COPD.AECs and fibroblasts obtained from COPD and control lung tissue were grown in co-culture with fetal lung fibroblast or human bronchial epithelial cell lines. mRNA and protein expression of inflammatory mediators, pro-fibrotic molecules and extracellular matrix (ECM) proteins were assessed.Co-culture resulted in the release of pro-inflammatory mediators interleukin (IL)-8/CXCL8 and heat shock protein (Hsp70) from lung fibroblasts, and decreased expression of ECM molecules (e.g. collagen, decorin) that was not different between control and COPD-derived primary cells. This pro-inflammatory effect was mediated by epithelial-derived IL-1α and increased upon epithelial exposure to cigarette smoke extract (CSE). When exposed to CSE, COPD-derived AECs elicited a stronger IL-1α response compared with control-derived airway epithelium and this corresponded with a significantly enhanced IL-8 release from lung fibroblasts.We demonstrate that, through IL-1α production, AECs induce a pro-inflammatory lung fibroblast phenotype that is further enhanced with CSE exposure in COPD, suggesting an aberrant epithelial–fibroblast interaction in COPD.

scholarly journals ACE2 Expression is elevated in Airway Epithelial Cells from aged and male donors but reduced in asthma

2020 ◽  
Author(s):  
Peter Wark ◽  
Prabuddha Pathinyake ◽  
Gerard Kaiko ◽  
Kristy Nichol ◽  
Ayesha Ali ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Serine Proteases ◽  
Airway Epithelial Cells ◽  
Lower Airway ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Obstructive Pulmonary Disease ◽  
Protein Levels ◽  
Asthma Patients

Rationale: COVID-19 is complicated by acute lung injury, and death in some individuals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine proteases to enter airway epithelial cells (AECs). Objective: To determine what factors are associated with ACE2 expression particularly in patients with asthma and chronic obstructive pulmonary disease (COPD). Methods: We obtained upper and lower AECs from 145 people from two independent cohorts, aged 2-89, Newcastle (n=115), and from Perth (n= 30) Australia. The Newcastle cohort was enriched with people with asthma (n=37) and COPD (n=38). Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry were assessed by quantitative PCR, protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AECs. Results: Increased gene expression of ACE2 was associated with older age (p=0.02) and male sex (p=0.03), but not pack-years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma (p=0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in asthma (p=0.02), while ADAM-17, a disintegrin that cleaves ACE2 from the surface was increased (p=0.02). ACE2 protein levels were lower in endobronchial biopsies from asthma patients. Conclusions: Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over-represented in those with COVID-19 complications.

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