Epithelial mesenchymal transition in smokers: large versus small airways and relation to airflow obstruction.
BACKGROUND
Small airway fibrosis is the main contributor in airflow obstruction in chronic obstructive pulmonary disease. Epithelial mesenchymal transition (EMT) has been implicated in this process, and in large airways, is associated with angiogenesis, ie, Type-3, which is classically promalignant.


OBJECTIVE
In this study we have investigated whether EMT biomarkers are expressed in small airways compared to large airways in subjects with chronic airflow limitation (CAL) and what type of EMT is present on the basis of vascularity.


METHODS
We evaluated epithelial activation, reticular basement membrane fragmentation (core structural EMT marker) and EMT-related mesenchymal biomarkers in small and large airways from resected lung tissue from 18 lung cancer patients with CAL and 9 normal controls. Tissues were immunostained for epidermal growth factor receptor (EGFR; epithelial activation marker), vimentin (mesenchymal marker), and S100A4 (fibroblast epitope). Type-IV collagen was stained to demonstrate vessels.


RESULTS
There was increased expression of EMT-related markers in CAL small airways compared to controls: EGFR (P<0.001), vimentin (P<0.001), S100A4 (P<0.001), and fragmentation (P<0.001), but this was less than that in large airways. Notably, there was no hypervascularity in small airway reticular basement membrane as in large airways. Epithelial activation and S100A4 expression were related to airflow obstruction.


CONCLUSIONS
EMT is active in small airways, but less so than in large airways in CAL, and may be relevant to the key pathologies of chronic obstructive pulmonary disease, small airway fibrosis, and airway cancers.
NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia.
Malik Quasir
MQ
Mahmood
NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia ; School of Health Sciences, Faculty of Health, University of Tasmania, Launceston, TAS, Australia.
Sukhwinder Singh
SS
Sohal
NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia.
Shakti Dhar
SD
Shukla
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK.
Chris
C
Ward
Royal Hobart Hospital, Hobart, TAS, Australia.
Ashutosh
A
Hardikar
NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia.
Wan Danial
WD
Noor
NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia.
Hans Konrad
HK
Muller
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.
Darryl A
DA
Knight
NHMRC Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, Hobart, TAS, Australia.
Eugene Haydn
EH
Walters
D000368:Aged; D001485:Basement Membrane / Q000737:chemistry; D014408:Biomarkers, Tumor / Q000032:analysis; D001706:Biopsy; D016022:Case-Control Studies; D024141:Collagen Type IV / Q000032:analysis; D004847:Epithelial Cells / Q000737:chemistry / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016014:Linear Models; D008168:Lung / Q000098:blood supply / Q000737:chemistry / Q000473:pathology*; D008175:Lung Neoplasms / Q000737:chemistry / Q000209:etiology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000032:analysis; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism / Q000473:pathology*; D014746:Vimentin / Q000032:analysis
D014408:Biomarkers, Tumor; D024141:Collagen Type IV; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D014746:Vimentin; C077591:S100A4 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors
EGFR; EMT; S100A4; fragmentation; small airways; vimentin