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SARS-CoV-2 (COVID-19) adhesion site protein upregulation in small airways, type 2 pneumocytes, and alveolar macrophages of smokers and COPD - possible implications for interstitial fibrosis


Brake, SJ and Eapen, MS and McAlinden, KD and Markos, J and Haug, G and Larby, J and Chia, C and Hardikar, A and Singhera, GK and Hackett, TL and Lu, W and Sohal, SS, SARS-CoV-2 (COVID-19) adhesion site protein upregulation in small airways, type 2 pneumocytes, and alveolar macrophages of smokers and COPD - possible implications for interstitial fibrosis, International Journal of Chronic Obstructive Pulmonary Disease, 17 Article 17. ISSN 1176-9106 (2022) [Refereed Article]

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2022 Brake et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (

DOI: doi:10.2147/COPD.S329783


Background: Smokers and patients with COPD are highly susceptible to SARS-CoV-2 infection, leading to severe COVID-19.
Methods: This cross-sectional study involved resected lung tissues from 16 patients with GOLD stage I or II COPD; of which 8 were current smokers COPD (COPD-CS), and 8 ex-smokers COPD (COPD-ES), 7 normal lung function smokers (NLFS), 9 patients with small airways disease (SAD), and 10 were never-smoking normal controls (NC). Immunostaining for ACE2, Furin, and TMPRSS2 was performed and analysed for percent expression in small airway epithelium (SAE) and counts for positively and negatively stained type 2 pneumocytes and alveolar macrophages (AMs) were done using Image ProPlus V7.0. Furthermore, primary small airway epithelial cells (pSAEC) were analysed by immunofluorescence after exposure to cigarette smoke extract (CSE).
Results: ACE2, Furin, and TMPRSS2 expression significantly increased in SAE and type 2 pneumocytes in all the subjects (except Furin for NLFS) compared to NC (p < 0.001). Similar significance was observed for ACE2 positive AM (p < 0.002), except COPD-ES, which decreased in ACE2 positive AMs (p < 0.003). Total type 2 pneumocytes and AMs significantly increased in the pathological groups compared to NC (p < 0.01), except SAD (p = 0.08). However, AMs are significantly reduced in COPD-ES (p < 0.003). Significant changes were observed for tissue co-expression of Furin and TMPRSS2 with ACE2 in SAE, type 2 pneumocytes and AMs. These markers also negatively correlated with lung function parameters, such as FEV1/FVC % predicted, FEF25-75%, DLCO% predicted. A strong co-localisation and expression for ACE2 (p < 0.0001), Furin (p < 0.01), and TMPRSS2 (p < 0.0001) was observed in pSAEC treated with 1% CSE than controls.
Discussion: The increased expression of ACE2, TMPRSS2 and Furin, in the SAE, type 2 pneumocytes and AMs of smokers and COPD are detrimental to lung function and proves that these patient groups could be more susceptible to severe COVID-19 infection. Increased type 2 pneumocytes suggest that these patients are vulnerable to developing post-COVID-19 interstitial pulmonary fibrosis or fibrosis in general. There could be a silently developing interstitial pathology in smokers and patients with COPD. This is the first comprehensive study to report such changes.

Item Details

Item Type:Refereed Article
Keywords:COVID-19, SARS-CoV-2, fibrosis, IPF, smoking, COPD, ACE2, type 2 pneumocytes, alveolar macrophages, epithelium
Research Division:Biomedical and Clinical Sciences
Research Group:Cardiovascular medicine and haematology
Research Field:Respiratory diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Diagnosis of human diseases and conditions
UTAS Author:Brake, SJ (Mr Sam Brake)
UTAS Author:Eapen, MS (Dr Mathew Eapen)
UTAS Author:McAlinden, KD (Mr Kielan McAlinden)
UTAS Author:Markos, J (Dr Jim Markos)
UTAS Author:Haug, G (Dr Greg Haug)
UTAS Author:Larby, J (Dr Josie Larby)
UTAS Author:Hardikar, A (Dr Ashutosh Hardikar)
UTAS Author:Lu, W (Dr Monica Lu)
UTAS Author:Sohal, SS (Dr Sukhwinder Sohal)
ID Code:148503
Year Published:2022
Web of Science® Times Cited:5
Deposited By:Health Sciences
Deposited On:2022-01-17
Last Modified:2022-11-01
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