Dysregulated cross-talk between alveolar epithelial cells and stromal cells in idiopathic pulmonary fibrosis reduces epithelial regenerative capacity.

In idiopathic pulmonary fibrosis (IPF) constant epithelial micro-injury and aberrant interactions within the stromal micro-environment lead to abnormal alveolar repair and fibrosis. We hypothesized that alveolar epithelial regenerative responses in IPF are impaired due to disturbed crosstalk between epithelial cells and their stromal niche. We established organoid cultures from unfractionated suspensions and isolated EpCAM cells from distal lung tissue of patients with and without IPF.

Paracrine Regulation of Alveolar Epithelial Damage and Repair Responses by Human Lung-Resident Mesenchymal Stromal Cells.

COPD is characterized by irreversible lung tissue damage. We hypothesized that lung-derived mesenchymal stromal cells (LMSCs) reduce alveolar epithelial damage via paracrine processes, and may thus be suitable for cell-based strategies in COPD. We aimed to assess whether COPD-derived LMSCs display abnormalities.

A Protective Role of FAM13A in Human Airway Epithelial Cells Upon Exposure to Cigarette Smoke Extract.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease characterized by chronic inflammation upon inhalation of noxious particles, e.g., cigarette smoke.

Retinoic acid signaling balances adult distal lung epithelial progenitor cell growth and differentiation.

Background: Despite compelling data describing pro-regenerative effects of all-trans retinoic acid (ATRA) in pre-clinical models of chronic obstructive pulmonary disease (COPD), clinical trials using retinoids for emphysema patients have failed. Crucial information about the specific role of RA signaling in adult rodent and human lung epithelial progenitor cells is largely missing.

Methods: Adult lung organoid cultures were generated from isolated primary mouse and human lung epithelial cells, and incubated with pharmacological pathway modulators and recombinant proteins.

SIRT1/FoxO3 axis alteration leads to aberrant immune responses in bronchial epithelial cells.

Inflammation and ageing are intertwined in chronic obstructive pulmonary disease (COPD). The histone deacetylase SIRT1 and the related activation of FoxO3 protect from ageing and regulate inflammation. The role of SIRT1/FoxO3 in COPD is largely unknown.

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

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.

Protocadherin-1 Localization and Cell-Adhesion Function in Airway Epithelial Cells in Asthma.

Background: The asthma gene PCDH1 encodes Protocadherin-1, a putative adhesion molecule of unknown function expressed in the airway epithelium. Here, we characterize the localization, differential expression, homotypic adhesion specificity and function of PCDH1 in airway epithelial cells in asthma.

Methods: We performed confocal fluorescence microscopy to determine subcellular localization of PCDH1 in 16HBE cells and primary bronchial epithelial cells (PBECs) grown at air-liquid interface.

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

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.

Cigarette smoke-induced epithelial expression of WNT-5B: implications for COPD.

Wingless/integrase-1 (WNT) signalling is associated with lung inflammation and repair, but its role in chronic obstructive pulmonary disease (COPD) pathogenesis is unclear. We investigated whether cigarette smoke-induced dysregulation of WNT-5B contributes to airway remodelling in COPD.We analysed WNT-5B protein expression in the lung tissue of COPD patients and (non)smoking controls, and investigated the effects of cigarette smoke exposure on WNT-5B expression in COPD and control-derived primary bronchial epithelial cells (PBECs).

Differential effects of fluticasone on extracellular matrix production by airway and parenchymal fibroblasts in severe COPD.

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal repair in the lung resulting in airway obstruction associated with emphysema and peripheral airway fibrosis. Because the presence and degree of airways disease and emphysema varies between COPD patients, this may explain the heterogeneity in the response to treatment. It is currently unknown whether and to what extent inhaled steroids can affect the abnormal repair process in the airways and lung parenchyma in COPD.

Role of aberrant metalloproteinase activity in the pro-inflammatory phenotype of bronchial epithelium in COPD.

Background: Cigarette smoke, the major risk factor for COPD, is known to activate matrix metalloproteinases in airway epithelium. We investigated whether metalloproteinases, particularly A Disintegrin and Metalloproteinase (ADAM)17, contribute to increased pro-inflammatory epithelial responses with respect to the release of IL-8 and TGF-α, cytokines implicated in COPD pathogenesis.

Methods: We studied the effects of cigarette smoke extract (CSE) and metalloproteinase inhibitors on TGF-α and IL-8 release in primary bronchial epithelial cells (PBECs) from COPD patients, healthy smokers and non-smokers.

House dust mite-promoted epithelial-to-mesenchymal transition in human bronchial epithelium.

The molecular basis of airway remodeling and loss of epithelial integrity in asthma is still undefined. We aimed to establish if exposure of human bronchial epithelium (16HBE cells) to asthma-related stimuli can induce epithelial-to-mesenchymal transition (EMT), a key process in tissue repair and remodeling associated with loss of intercellular contacts. We studied the effects of fibrogenic cytokine TGF-beta and protease-containing aeroallergen house dust mite (HDM) on mesenchymal and epithelial markers, cytoskeleton organization, and activation of beta-catenin-driven reporter TopFLASH.

Expression of ADAMs ("a disintegrin and metalloprotease") in the human lung.

In view of the associations of "a disintegrin and metalloprotease" (ADAM) with respiratory diseases, we assessed the expression of various ADAMs in human lung tissue. Lung tissue was obtained from nine individuals who underwent surgery for lung cancer or underwent lung transplantation for emphysema. Also, 16HBE 14o- (human bronchial epithelial) and A549 (alveolar type II epithelium-like) cell lines were used.

Smad gene expression in pulmonary fibroblasts: indications for defective ECM repair in COPD.

Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by defective extracellular matrix (ECM) turnover as a result of prolonged cigarette smoking. Fibroblasts have a central role in ECM turnover. The TGFbeta induced Smad pathway provides intracellular signals to regulate ECM production.

Different modulation of decorin production by lung fibroblasts from patients with mild and severe emphysema.

We have previously reported diminished immunohistochemical staining of decorin in lung tissue from patients with severe emphysema. The aim of this study is to investigate whether this diminished staining is due to a quantitative abnormal production of decorin by pulmonary fibroblasts in vitro. Therefore, we measured decorin (Western blot), collagen type I (ELISA), and fibronectin (ELISA) production by fibroblasts obtained from lung tissue of patients with severe and mild emphysema at basal culture conditions and after modulation with transforming growth factor-beta1, basic fibroblast growth factor, and interferon-gamma.

Interaction of airway epithelial cells (A549) with spores and mycelium of Aspergillus fumigatus.

Objective: To study the interaction of airway epithelial cell line A549 with fragments of mycelium, spores of Aspergillus fumigatus in vitro and to determine if toll-like receptors (TLRs) are involved in the process.

Methods: A549 cells were exposed to fragments of A. fumigatus mycelium, zymosan and inactivated A.

Different proliferative capacity of lung fibroblasts obtained from control subjects and patients with emphysema.

To characterize the possible role of a dysregulated proliferative capacity of pulmonary fibroblasts in insufficient tissue repair in lungs from patients with pulmonary emphysema, the authors undertook in vitro proliferative studies with pulmonary fibroblasts obtained from lung tissue of patients with emphysema. A comparison was made with fibroblasts from control subjects. The authors determined the in vitro proliferative capacity of fibroblasts at basal culture conditions and after modulation with interleukin-1beta, interferon-gamma, transforming growth factor-beta(1), and basic fibroblast growth factor.