Transforming growth factor (TGF) ß1 and Smad signalling pathways: A likely key to EMT-associated COPD pathogenesis.

ABSTRACT

BACKGROUND AND OBJECTIVE: COPD is characterized by poorly reversible airflow obstruction usually due to cigarette smoking. Transforming growth factor (TGF)-ß1 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-ß1 pathway is via the phosphorylated (p) Smad transcription factor system. METHODS: We have investigated TGF-ß1 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-ß1 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-ß1 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-ß1 expression, was related to airflow obstruction and a canonical EMT biomarker (S100 A4) expression. CONCLUSION: Activation of the Smad pathway in the airways is linked to EMT activity and loss of lung function. The disconnection between TGF-ß1 and pSmad in terms of relationships to EMT activity and lung function suggests that factors other than or in addition to TGF-ß1 are driving the process.