Transforming growth factor (TGF) β1 and Smad signalling pathways: A likely key to EMT-associated COPD pathogenesis

Background and objective COPD is characterized by poorly reversible airflow obstruction usually due to cigarette smoking. Transforming growth factor (TGF)-1 has been implicated in the pathogenesis of COPD, and in particular a process called epithelial mesenchymal transition (EMT), which may well be an intermediatory between smoking and both airway fibrosis and lung cancer. The downstream classical or canonical' TGF-1 pathway is via the phosphorylated (p) Smad transcription factor system. MethodsWe have investigated TGF-1 expression and its pSmad fingerprint' in bronchoscopic airway biopsies from patients with COPD, and in smoking and non-smoking controls. A cross-sectional immunohistochemical study compared TGF-1 and pSmad 2, 3 (excitatory) and 7 (inhibitory) expression in cells and blood vessels of three compartments of large airways: epithelium (especially the basal region), reticular basement membrane (Rbm) and underlying lamina propria (LP). Results TGF-1 expression was generally higher in COPD subjects throughout the airway wall (P<0.01), while pSmad 2/3 expression was associated with smoking especially in current smoking COPD (P<0.05). Expression of inhibitory pSmad 7 was also prominently reduced in patients with COPD in contrast to smokers and controls (P<0.01). In addition, pSmad, but not TGF-1 expression, was related to airflow obstruction and a canonical EMT biomarker (S100 A4) expression. ConclusionActivation of the Smad pathway in the airways is linked to EMT activity and loss of lung function. The disconnection between TGF-1 and pSmad in terms of relationships to EMT activity and lung function suggests that factors other than or in addition to TGF-1 are driving the process. COPD is fundamentally due to small airway fibrosis mainly in smokers. Pathologically, it is associated with active epithelial mesenchymal transition (EMT). Relatively, little has been studied regarding the transforming growth factor (TGF)-1-pSmad pathway in smokers and COPD. This study facilitates the understanding of EMT-associated pathogenesis of COPD in terms of this pathway.