Increased myofibroblasts in the small airways and relation to remodelling and functional changes in smokers and COPD patients: potential role of epithelial-mesenchymal transition (EMT)
- Mathew Suji Eapen1,
- Wenying Lu1,
- Tillie L. Hackett2,
- Gurpreet Kaur Singhera2,
- Malik Q. Mahmood3,
- Ashutosh Hardikar1,4,
- Chris Ward5,
- Eugene Haydn Walters6,7 and
- Sukhwinder Singh Sohal1,7⇑
- 1Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia
- 2Department of Anesthesiology, Pharmacology & Therapeutics, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada, and UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada<CE: Please check affiliation 2 and affiliation 2 links.>
- 3School of Medicine, Deakin University, Waurn Ponds, Australia
- 4Department of Cardiothoracic Surgery, Royal Hobart Hospital, Hobart, Tasmania, Australia
- 5Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
- 6School of Medicine, and Menzies Institute of Medical Research, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia
- 7Equal contributors
- Dr Sukhwinder Singh Sohal, Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Locked Bag – 1322, Newnham Drive, Launceston, Tasmania 7248, Australia. E-mail: sssohal{at}utas.edu.au
Abstract
Introduction Previous 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.
Methods Lung 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.
Results We 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.
Conclusions This 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.
Footnotes
This manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Eapen has nothing to disclose.
Conflict of interest: Dr. Lu has nothing to disclose.
Conflict of interest: Dr. Hackett has nothing to disclose.
Conflict of interest: Dr. Singhera has nothing to disclose.
Conflict of interest: Dr. Mahmood has nothing to disclose.
Conflict of interest: Dr. Hardikar has nothing to disclose.
Conflict of interest: Dr. Ward has nothing to disclose.
Conflict of interest: Dr. Walters has nothing to disclose.
Conflict of interest: Dr. Sohal reports personal fees from Chiesi, outside the submitted work.
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- Received November 25, 2020.
- Accepted March 10, 2021.
- Copyright ©The authors 2021
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