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. 2021 Jan 1;320(1):L152-L157.
doi: 10.1152/ajplung.00455.2020. Epub 2020 Oct 28.

Angiotensin-converting enzyme 2 expression in COPD and IPF fibroblasts: the forgotten cell in COVID-19

Noof Aloufi  1   2 , Hussein Traboulsi  1 , Jun Ding  1   3 , Gregory J Fonseca  1   4 , Parameswaran Nair  5 , Steven K Huang  6 , Sabah N A Hussain  1   2 , David H Eidelman  4 , Carolyn J Baglole  1   2   4   7
Affiliations

Angiotensin-converting enzyme 2 expression in COPD and IPF fibroblasts: the forgotten cell in COVID-19

Noof Aloufi et al. Am J Physiol Lung Cell Mol Physiol. .

Abstract

The COVID-19 pandemic is associated with severe pneumonia and acute respiratory distress syndrome leading to death in susceptible individuals. For those who recover, post-COVID-19 complications may include development of pulmonary fibrosis. Factors contributing to disease severity or development of complications are not known. Using computational analysis with experimental data, we report that idiopathic pulmonary fibrosis (IPF)- and chronic obstructive pulmonary disease (COPD)-derived lung fibroblasts express higher levels of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 entry and part of the renin-angiotensin system that is antifibrotic and anti-inflammatory. In preclinical models, we found that chronic exposure to cigarette smoke, a risk factor for both COPD and IPF and potentially for SARS-CoV-2 infection, significantly increased pulmonary ACE2 protein expression. Further studies are needed to understand the functional implications of ACE2 on lung fibroblasts, a cell type that thus far has received relatively little attention in the context of COVID-19.

Keywords: ACE2; COPD; IPF; SARS-CoV-2; fibroblast.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Fig. 1.
Fig. 1.
Cell-specific ACE2 expression in COPD and IPF lungs. A: expression of ACE2: data analysis of scRNA-seq of COPD, IPF, and control lungs revealed that there were more ACE2+ cells in COPD. B: percentage (%) of ACE2+ cells: ACE2+ cells accounted for 2.94% of the IPF cells, 2.40% of the COPD cells, and 2.30% of control cells. C: cell-specific ACE2+ percentage (%): ACE2+ cells are mostly enriched in lung epithelial cells (goblet cells, 6.6%; basal cells, 5.6%). Fibroblasts (4.0%) are also enriched with ACE2, ranking 9th of all 38 cell types. Results were analyzed with a one-sided Mann–Whitney U test. ACE2, angiotensin-converting enzyme 2; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis.
Fig. 2.
Fig. 2.
ACE2 protein is higher in COPD- and IPF-derived lung fibroblasts. A and B: COPD fibroblasts: lung fibroblasts derived from subjects with COPD had significantly higher ACE2 protein expression compared with lung fibroblasts from never-smokers (*P < 0.05). There was a trend toward higher ACE2 in smoker-derived fibroblasts. Smoker and COPD-derived lung fibroblasts were from current smokers. Data were analyzed by a one-way ANOVA followed by Dunn’s test. C and D: IPF fibroblasts: lung fibroblasts derived from subjects with IPF had significantly higher ACE2 protein compared with control cells. Data were analyzed by a two-tailed t test. Results are expressed as the means ± SE (***P < 0.001 compared with control cells) n = 4/group. ACE2, angiotensin-converting enzyme 2; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis.
Fig. 3.
Fig. 3.
Chronic cigarette smoke exposure increases pulmonary ACE2 protein expression. A: in vitro CSE exposure: primary human lung fibroblasts from a never-smoker were exposed to 2% CSE for 8-48 h and ACE2 protein evaluated by Western blot; normalization was done to tubulin. There was no change in total ACE2 expression upon exposure to CSE. B and C: acute exposure: mice were exposed to cigarette smoke using the SCIREQ inExpose whole body exposure system twice per day for 3 days. Control mice were exposed to room air. Mice were euthanized and the lungs were processed for Western blot analysis. There was no change in the total levels of ACE2 in the cigarette smoke-exposed mice compared with the control mice. Number of mice in each group is indicated. Data were analyzed by a two-tailed t test. D and E: chronic exposure: mice were exposed to cigarette smoke for 5 days/wk for 2 or 4 wk and the lungs processed for Western Blot; tubulin and actin were used as loading controls; data were normalized using actin. Control mice were exposed to only room air. There was a noticeable increase in ACE2 protein expression after 2 wk of smoke exposure; this increase in ACE2 reached statistical significance by 4 wk of cigarette smoke exposure compared with both air control mice (**P < 0.01) as well as mice exposed to CS for 2 wk (**P < 0.05). Number of mice in each group is indicated. Data were analyzed by a one-way ANOVA followed by the Holm–Sidak post hoc test. ACE2, angiotensin-converting enzyme 2; CSE, cigarette smoke extract.
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