Increased myofibroblasts in the small airways, and relationship to remodelling and functional changes in smokers and COPD patients: potential role of epithelial–mesenchymal transition

Abstract

IntroductionPrevious reports showed epithelial mesenchymal transition (EMT) as an active process that contributes to small airway (SA) fibrotic pathology. Myofibroblasts are highly active pro-fibrotic cells that secrete excessive and altered extracellular matrix (ECM). Here we relate SA myofibroblast presence with airway remodelling, physiology and EMT activity in smokers and COPD patients.MethodsLung resections from non-smoker controls (NC), normal lung function smokers (NLFS), COPD current (CS) and ex-smokers (ES) were stained with anti-human αSMA, collagen 1, and fibronectin. αSMA+ive cells were computed in reticular basement membrane (Rbm), lamina propria (LP), and adventitia and presented per mm of Rbm and mm2 of LP. Collagen-1 and fibronectin are presented as a percentage change from normal. All analysis including airway thickness were measured using Image-pro-plus 7.0.ResultsWe found an increase in sub-epithelial LP (especially) and adventitia thickness in all pathological groups compared to NC. Increases in αSMA+ive myofibroblasts were observed in sub-epithelial Rbm, LP, and adventitia in both the smoker and COPD groups compared to NCs. Further, the increase in the myofibroblast population in the LP was strongly associated with decrease in lung function, LP thickening, increase in ECM protein deposition, and finally EMT activity in epithelial cells.ConclusionsThis is the first systematic characterisation of small airway myofibroblasts in COPD based on their localisation, with statistically significant correlations between them and other pan-airway structural, lung function, and ECM protein changes. Finally, we suggest that EMT may be involved in such changes.

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

“…Airway Smooth Muscle (ASM) and Fibroblasts. Persistent airway thickening and remodeling, which are hallmark pathological features in asthma and COPD, contribute to airflow obstruction and impaired lung function [ 14 , 63 , 64 , 65 ]. Increases in ASM and airway fibroblasts in the sub-epithelial layer can be attributed to increases in proliferation, extracellular matrix deposition, and hypertrophy [ 66 , 67 , 68 , 69 , 70 ].…”

“…Functional changes involving airway thickening and stiffening contribute to airflow obstruction and acute exacerbation. These structural and functional alterations are worsened in asthma and COPD patients with corticosteroid insensitivity [ 14 , 15 , 16 ].…”

SB203580—A Potent p38 MAPK Inhibitor Reduces the Profibrotic Bronchial Fibroblasts Transition Associated with Asthma

“…Under profibrotic pathological conditions, the populations of myofibroblasts remain constitutively active and in consequence, lead to the overproduction of ECM proteins, tissue malformations and functional impairment. This is documented in the skin [ 32 ], liver [ 33 ], heart [ 34 ] and kidney fibrosis [ 35 ], lung diseases as a chronic obstructive pulmonary disease (COPD) [ 36 ], idiopathic pulmonary fibrosis (IPF) [ 37 ] and also in subepithelial fibrosis in asthma [ 6 ]. Routinely used therapies for asthma primarily affect the inflammatory processes in the airways and the symptoms of asthma but are insufficient or ineffective in case of the development of bronchial subepithelial fibrosis [ 6 ], which can be driven also in an inflammation-independent manner [ 38 , 39 , 40 ].…”

Roles of Mesenchymal Cells in the Lung: From Lung Development to Chronic Obstructive Pulmonary Disease

“…These profibrotic growth factors may induce a profibrotic phenotype in adjacent airway fibroblasts or promote the differentiation of bronchial smooth muscle cells into myofibroblasts. Indeed, a recent study showed an increase of the αSMA+ myofibroblast population in small airways of patients with COPD compared with controls [ 155 ].…”