Increased Angiotensin-Converting Enzyme 2 and Loss of Alveolar Type II Cells in COVID-19–related Acute Respiratory Distress Syndrome

<b>Rationale:</b> ACE2 (angiotensin-converting enzyme 2), the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is expressed in type 2 alveolar epithelial cells (AT2) that may play key roles in postinjury repair. An imbalance between ACE2 and ACE has also been hypothesized to contribute to lung injury. <b>Objectives:</b> To characterize the expression and distribution of ACE2 and ACE and to compare AT2 with endothelial cell expression in coronavirus disease (COVID-19)-related or -unrelated acute respiratory distress syndrome (ARDS) and controls. <b>Methods:</b> Lung tissue stainings (using multiplex immunofluorescence) and serum concentrations of ACEs were determined retrospectively in two different cohorts of patients. AT2 and endothelial cells were stained in lung tissue for ProSPC (pro-surfactant protein C) and CD31, respectively. <b>Measurements and Main Results:</b> Pulmonary ACE2 expression was increased in patients with COVID-19-related and -unrelated ARDS (0.06% of tissue area and 0.12% vs. 0.006% for control subjects; <i>P</i> = 0.013 and <i>P</i> < 0.0001, respectively). ACE2 was upregulated in endothelial cells (0.32% and 0.53% vs. 0.01%; <i>P</i> = 0.009 and <i>P</i> < 0.0001) but not in AT2 cells (0.13% and 0.08% vs. 0.03%; <i>P</i> = 0.94 and <i>P</i> = 0.44). Pulmonary expression of ACE was decreased in both COVID-19-related and -unrelated ARDS (<i>P</i> = 0.057 and <i>P</i> = 0.032). Similar increases in ACE2 and decreases in ACE were observed in sera of COVID-19 (<i>P</i> = 0.0054 and <i>P</i> < 0.0001) and non-COVID-19 ARDS (<i>P</i> < 0.0001 and <i>P</i> = 0.016). In addition, AT2 cells were decreased in patients with COVID-19-related ARDS compared with COVID-19-unrelated ARDS (1.395% vs. 2.94%, <i>P</i> = 0.0033). <b>Conclusions:</b> ACE2 is upregulated in lung tissue and serum of both COVID-19-related and -unrelated ARDS, whereas a loss of AT2 cells is selectively observed in COVID-19-related ARDS.