Effects of Asthma Combination Therapy on Extracellular Matrix Remodeling in Human Lung Fibroblasts (original) (raw)
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The extracellular matrix of the lung and airway responsiveness in asthma
Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Università di Napoli, Secondo ateneo, 2009
The extracellular matrix is the main determinant of the structure and of mechanical behaviour of the lung. The extracellular matrix is also responsible for the mechanical interdependence between airway and parenchyma due to the alveolar attachments to the airways. Asthma is characterized by bronchial hyperresponsiveness, airway remodelling and inflammation, and an altered extracellular matrix may play a role in all these functional and structural abnormalities. The excessive airway narrowing observed in asthma may be related to the altered viscoelastic properties of lung parenchyma and airway wall, determining a decrease in the mechanical load opposing the airways' smooth muscle contraction. Indeed, an altered extracellular matrix deposition in asthma in humans, has been demonstrated. In addition, in the asthmatic lung, the matrix seems to contribute to airway inflammation, airway remodelling, and to those alterations of the smooth muscle function of the airway and morphology ty...
Altered matrix production in the distal airways of individuals with asthma
Thorax, 2010
Background and aims Although increasing evidence suggests involvement of the distal airway in all stages of asthma, it is not known whether structural changes (defined as airway remodelling) occur in the distal airways of subjects with mild asthma and those with atopy. The aim of this study was to compare control subjects and those with mild asthma in relation to fibroblast phenotypes and remodelling in central and distal airways. Methods Distal and central fibroblasts from controls (n¼12) and patients with mild asthma (n¼11) were cultured and incubated for 24 h with 0.4% serum, or stimulated with transforming growth factor b1 (TGFb1). [ 35 S]Sulfate-labelled proteoglycans in culture medium were analysed by ion exchange chromatography and sodium dodecyl sulfateepolyacrylamide gel electrophoresis. Proliferation was measured with crystal violet, and exhaled nitric oxide was measured by the fractional nitric oxide technique. Results Vesican production from distal fibroblasts was significantly elevated in patients with asthma compared with controls (p<0.001), and the percentage collagenpositive area in distal asthma tissue was also enhanced compared with controls (p<0.01). In addition, distal asthma fibroblasts had reduced proliferation capacity compared with those of controls (by 24%; p<0.01). Furthermore, the alveolar nitric oxide concentration was correlated to distal biglycan and perlecan production of subjects with asthma (r¼À0.857, p<0.05 and r¼À0.750, p<0.05 respectively) Conclusion It is shown that centrally and distally derived fibroblasts differ in their proteoglycan production and proliferation between central and distal tissue, and in those with asthma compared with controls. It is also demonstrated that remodelling is present in distal lung of subjects with mild asthma. This may be of importance in airway remodelling and asthma progression.
Original Paper Airway proteoglycans are differentially altered in fatal asthma
2020
It has been suggested that airway remodelling is responsible for the persistent airway obstruction and decline in lung function observed in some asthmatic patients. The small airways are thought to contribute significantly to this functional impairment. Proteoglycans (PGs) are important components of the extracellular matrix (ECM) in the lungs. Besides controlling biophysical properties of the ECM, they play important roles in the regulation of some cytokines. Increased subepithelial PG deposition in the airways of mild asthmatics has been reported. However, there are no data on the PG content in small airways in asthma. This study has compared the content and distribution of PGs in large and small airways of patients who died of asthma with those in control lungs. Immunohistochemistry and image analysis were used to determine the content of lumican, decorin, biglycan, and versican in large (internal perimeter >6 mm) and small (internal perimeter ≤6 mm) airways of 18 patients who...
Airway proteoglycans are differentially altered in fatal asthma
Journal of Pathology, 2005
It has been suggested that airway remodelling is responsible for the persistent airway obstruction and decline in lung function observed in some asthmatic patients. The small airways are thought to contribute significantly to this functional impairment. Proteoglycans (PGs) are important components of the extracellular matrix (ECM) in the lungs. Besides controlling biophysical properties of the ECM, they play important roles in the regulation of some cytokines. Increased subepithelial PG deposition in the airways of mild asthmatics has been reported. However, there are no data on the PG content in small airways in asthma. This study has compared the content and distribution of PGs in large and small airways of patients who died of asthma with those in control lungs. Immunohistochemistry and image analysis were used to determine the content of lumican, decorin, biglycan, and versican in large (internal perimeter >6 mm) and small (internal perimeter ≤6 mm) airways of 18 patients who had died of asthma (A) and ten controls (C). The results were expressed as PG area (µm2)/epithelial basement membrane length (µm). The main differences between asthmatics and controls were observed in the small airways. There was a significant decrease in decorin and lumican contents in the external area of small airways in asthmatics (decorin: A = 1.05 ± 0.27 µm, C = 3.97 ± 1.17 µm, p = 0.042; lumican: A = 1.97 ± 0.37 µm, C = 5.66 ± 0.99 µm, p = 0.002). A significant increase in versican content in the internal area of small and large airways in asthmatics was also observed (small: A = 7.48 ± 0.84 µm, C = 5.16 ± 0.61 µm, p = 0.045; large: A = 18.38 ± 1.94 µm, C = 11.90 ± 2.86 µm, p = 0.028). The results show that PGs are differentially expressed in the airways of fatal asthma and may contribute to airway remodelling. These data reinforce the importance of the small airways in airway remodelling in asthma. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Controlled and uncontrolled asthma display distinct alveolar tissue matrix compositions
Respiratory Research, 2014
Objective: Whether distal inflammation in asthmatics also leads to structural changes in the alveolar parenchyma remains poorly examined, especially in patients with uncontrolled asthma. We hypothesized that patients who do not respond to conventional inhaled corticosteroid therapy have a distinct tissue composition, not only in central, but also in distal lung. Methods: Bronchial and transbronchial biopsies from healthy controls, patients with controlled atopic and patients with uncontrolled atopic asthma were processed for immunohistochemical analysis of fibroblasts and extracellular matrix molecules: collagen, versican, biglycan, decorin, fibronectin, EDA-fibronectin, matrix metalloproteinase (MMP)-9 and tissue-inhibitor of matrix metalloproteinase (TIMP)-3.
American Journal of Respiratory Cell and Molecular Biology, 2004
Extracellular matrix (ECM) expansion contributes to airway remodeling in asthma. This study examines the effect of leukotriene D4 (LTD4), combined with epidermal growth factor (EGF), on proteoglycan synthesis by cultured human bronchial smooth muscle cells (BSMCs). LTD4 plus EGF stimulated proliferation of BSMCs with increased versican synthesis. Further, versican mRNA splice variants, V0 and V1, were differently regulated in BSMCs by LTD4 plus EGF. Synthesis of [ 35 S]-methionine labeled versican V0, as a percentage of total versican, was doubled. This upregulation was confirmed by Western analysis. Synthetic changes were paralleled by alterations in versican V0 mRNA. The effects of LTD4 and EGF on proteoglycan synthesis were inhibited by montelukast. Similar upregulation of versican V0 was observed in arterial smooth muscle cells (ASMCs) stimulated with LTD4 plus EGF as measured by western and reverse transcriptase-polymerase chain reaction analyses. Changes in ECM in the asthmatic airway may parallel those in atherosclerotic lesions where proliferating ASMCs synthesize a versican-rich expanded ECM. Inhibition of these processes could lead to reduced tissue expansion in the early phases of asthma progression. Asthma is characterized by airway wall thickening and obstruction. Part of this thickening is due to airway smooth muscle hyperplasia and hypertrophy (1, 2) and part is due to deposits of connective tissue in the extracellular matrix (ECM) (3-12). Recent studies have shown an increase in lung proteoglycans and hyaluronan, two components of the ECM, in lung fibrosis (13-16) and in mild forms of asthma (3, 12, 16, 17). Also, bronchial fibroblasts from patients with asthma synthesize increased amounts of proteoglycans (18), suggesting that the deposition of these molecules may be an early remodeling response. These events precede the deposition of collagens in later stages of fibrosis (8, 9). ECM enriched in proteoglycans tends to favor cellular proliferative responses, whereas ECM enriched in collagen tends to suppress proliferation (19). It may be that targeting processes
The Role of Extracellular Matrix in Lung Diseases
Biology and Medicine, 2014
The role of extracellular matrix in lung disease has been an area of increasing research interest. Numerous studies have demonstrated the importance of extracellular matrix in pulmonary pathologies. Evaluation of the intracellular function and basic structural properties of proteoglycan adhesion proteins and structural proteins may reveal new approaches to the treatment of pulmonary disease. This manuscript summarizes the role of extracellular matrix in pulmonary diseases based on the currently available literature.
Cells
Changes in extracellular matrix (ECM) components in the lungs are associated with the progression of respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). Experimental and clinical studies have revealed that structural changes in ECM components occur under chronic inflammatory conditions, and these changes are associated with impaired lung function. In bronchial asthma, elastic and collagen fiber remodeling, mostly in the airway walls, is associated with an increase in mucus secretion, leading to airway hyperreactivity. In COPD, changes in collagen subtypes I and III and elastin, interfere with the mechanical properties of the lungs, and are believed to play a pivotal role in decreased lung elasticity, during emphysema progression. In ARDS, interstitial edema is often accompanied by excessive deposition of fibronectin and collagen subtypes I and III, which can lead to respiratory failure in the intensive c...
Cultured Lung Fibroblasts from Ovalbumin-Challenged “Asthmatic” Mice Differ Functionally from Normal
American Journal of Respiratory Cell and Molecular Biology, 2007
Asthmatic airway remodeling is characterized by goblet cell hyperplasia, angiogenesis, smooth muscle hypertrophy, and subepithelial fibrosis. This study evaluated whether acquired changes in fibroblast phenotype could contribute to this remodeling. Airway and parenchymal fibroblasts from control or chronically ovalbumin (OVA)sensitized and challenged ''asthmatic'' mice were assessed for several functions related to repair and remodeling 6 exogenous transforming growth factor (TGF)-b. All OVA-challenged mouse fibroblasts demonstrated augmented gel contraction (P , 0.05) and chemotaxis (P , 0.05); increased TGF-b 1 (P , 0.05), fibronectin (P , 0.05), and vascular endothelial growth factor (P , 0.05) release; and expressed more a-smooth muscle actin (P , 0.05). TGF-b 1 stimulated both control and asthmatic fibroblasts, which retained all differences from control fibroblasts for all features(P , 0.05, all comparisons). Parenchymal fibroblasts proliferated more rapidly (P , 0.05), while airway fibroblasts proliferated similarly compared with control fibroblasts (P 5 0.25). Thus, in this animal model, OVAchallenged mouse fibroblasts acquire a distinct phenotype that differs from control fibroblasts. The augmented profibrotic activity and mediator release of asthmatic fibroblasts could contribute to airway remodeling in asthma.