Transforming growth factor (TGF) β1and Smad signalling pathways: A likely key to EMT-associated COPD pathogenesis.
COPD is characterized by poorly reversible airflow obstruction usually due to cigarette smoking. Transforming growth factor (TGF)-β1 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-β1 pathway is via the phosphorylated (p) Smad transcription factor system.



We have investigated TGF-β1 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-β1 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).



TGF-β1 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-β1 expression, was related to airflow obstruction and a canonical EMT biomarker (S100 A4) expression.



Activation of the Smad pathway in the airways is linked to EMT activity and loss of lung function. The disconnection between TGF-β1 and pSmad in terms of relationships to EMT activity and lung function suggests that factors other than or in addition to TGF-β1 are driving the process.
NHMRC Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
Malik Q
MQ
Mahmood
Queensland Institute of Medical Research, Iron Metabolism Laboratory, Brisbane, Queensland, Australia.
David
D
Reid
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Chris
C
Ward
NHMRC Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
Hans K
HK
Muller
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.
Darryl A
DA
Knight
NHMRC Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.|Faculty of Health, School of Health Sciences, University of Tasmania, Launceston, Tasmania, Australia.
Sukhwinder S
SS
Sohal
NHMRC Centre of Research Excellence for Chronic Respiratory Disease, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
Eugene H
EH
Walters
D000328:Adult; D000368:Aged; D001706:Biopsy / Q000379:methods; D001999:Bronchoscopy / Q000379:methods; D000073865:Cigarette Smoking / Q000378:metabolism / Q000503:physiopathology; D003430:Cross-Sectional Studies; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000503:physiopathology; D012129:Respiratory Function Tests / Q000379:methods; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1
Smad 2/3; Smad 7; chronic obstructive pulmonary disease; epithelial mesenchymal transition; transforming growth factor β1