Mechanical Ventilation Stimulates Expression of ACE2, the Receptor for SARS-Cov-2

Abstract

The SARS-Cov-2 virus, which causes COVID 19, uses the cell surface protein ACE2 as receptor for entry into cells. Critically ill COVID-19 patients often require prolonged mechanical ventilation which can cause mechanical stress to lung tissue. In vitro studies have shown that expression of ACE2 in alveolar cells is increased following mechanical stretch and inflammation. Therefore, we analyzed transcriptome datasets of 480 (non-COVID-19) lung tissues in the GTex tissue gene expression database. We found that mechanical ventilation of the tissue donors increased the expression of ACE2 by more than two-fold (p<10-6). Analysis of transcriptomes of mechanically ventilated mice deposited in the GEO database indicates that this alveolar cell response to stretch and inflammation is mediated by the chemokine midkine. We also found in transcriptomes of the LINCS database of pharmacological perturbations that corticosteroids down-regulate midkine in pulmonal cells, consistent with transcriptome data of animal studies in GEO. Thus, mechanical ventilation of patients with COVID-19 pneumonia may eo ipso facilitate viral propagation in the lung, further accelerating the pulmonal pathology that has necessitated mechanical ventilation in the first place. This vicious cycle offers a possible rationale for interventions that disrupt the corticosteroid-midkine-ACE2 axis and provides a mechanism that supports the calls for gentler ventilation protocols.