Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects

Abstract

Rationale: Smokers and patients with chronic obstructive pulmonary disease (COPD) are at increased risk for severe Coronavirus Disease 2019 (COVID-19). Objectives: We investigated the expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptor ACE2 and the protease TMPRSS2 in lung tissue from never smokers and smokers with and without COPD. Methods: In a cross-sectional, observational study we measured mRNA expression of ACE2 and TMPRSS2 by RT-PCR in lung tissue samples from 120 well phenotyped subjects. Next, protein levels of ACE2 were visualized by immunohistochemistry on paraffin sections from 87 subjects and quantified in alveolar and bronchial epithelium. Finally, primary human bronchial epithelial cells (HBECs) were cultured at air liquid interface and exposed to air or cigarette smoke. Results: ACE2 mRNA expression was significantly higher in lung tissue from current smokers and subjects with moderate to very severe COPD and correlated with physiological parameters of airway obstruction and emphysema. Pulmonary expression levels of TMPRSS2 were significantly higher in patients with (very) severe COPD and correlated significantly with ACE2 expression. Importantly, protein levels of ACE2 were elevated in both alveolar and bronchial epithelium of current smokers and subjects with moderate to very severe COPD. Finally, TMPRSS2 mRNA expression increased in in vitro cultured HBECs upon acute exposure to cigarette smoke. Conclusions: We demonstrate increased expression of ACE2 in lungs of smokers and COPD subjects, which might facilitate host cell entry of SARS-CoV-2. These findings help identifying populations at risk for severe COVID-19.

Inhaled corticosteroids downregulate SARS-CoV-2-related gene expression in COPD: results from a RCT

“…SARS-CoV-2 achieves host cell entry primarily via membrane-bound ACE2. We previously showed that ACE2 gene and protein expression was increased in the bronchial epithelium (6) and lung tissue (7) of people with COPD, a finding confirmed by other investigators (27, 28). Increased availability of ACE2 may increase the susceptibility to infection and the risk of severe COVID-19 (29, 30).…”

Smoking and COVID-19: The Real Deal

“…Among published studies, there is an overrepresentation of analyses of RNA datasets from lungs of smokers compared to nonsmokers or from resident lung cells. Findings from these studies have been variable with most showing persuasive evidence of ACE2 induction among smokers while others show no significant difference (25)(26)(27)(28)(29)(30)(31). Further, the few studies that examined ACE2 protein expression in the lungs or in the resident cells of smokers versus nonsmokers have been quite small but show a modest increase in ACE2 levels with active smoking (32).…”

Age‐related differences in the immune response could contribute to determine the spectrum of severity of COVID‐19

“…Although a progressive decrease of the receptor expression with age has been described, 64 other authors reported a lower density of ACE2 in children compared to adult patients 65 . Most of the studies reported that the expression of ACE2 is enhanced in smokers and obese patients, 62 while data on the tissue levels of ACE2 in systemic and pulmonary disorders are not univocal 66–70 . However, the interest on ACE2 receptor in COVID‐19 is not limited to its role of binding site for SARS‐CoV‐2.…”