Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation

Abstract

Mortality due to Covid-19 is highly associated with advanced age, owing in large part to severe lower respiratory tract infection. SARS-CoV-2 utilizes the host ACE2 receptor for infection. Whether ACE2 abundance in the lung contributes to age-associated vulnerability is currently unknown. We set out to characterize the RNA and protein expression profiles of ACE2 in aging human lung in the context of phenotypic parameters likely to affect lung physiology. Examining publicly available RNA sequencing data, we discovered that mechanical ventilation is a critical variable affecting lung ACE2 levels. Therefore, we investigated ACE2 protein abundance in patients either requiring mechanical ventilation or spontaneously breathing. ACE2 distribution and expression were determined in archival lung samples by immunohistochemistry (IHC). Tissues were selected from the specimen inventory at a large teaching hospital collected between 2010–2020. Twelve samples were chosen from patients receiving mechanical ventilation for acute hypoxic respiratory failure (AHRF). Twenty samples were selected from patients not requiring ventilation. We compared samples across age, ranging from 40–83 years old in the ventilated cohort and 14–80 years old in the non-ventilated cohort. Within the alveolated parenchyma, ACE2 expression is predominantly observed in type II pneumocytes (or alveolar type II / AT2 cells) and alveolar macrophages. All 12 samples from our ventilated cohort showed histologic features of diffuse alveolar damage including reactive, proliferating AT2 cells. In these cases, ACE2 was strongly upregulated with age when normalized to lung area (p = 0.004) or cellularity (p = 0.003), associated with prominent expression in AT2 cells. In non-ventilated individuals, AT2 cell reactive changes were not observed and ACE2 expression did not change with age when normalized to lung area (p = 0.231) or cellularity (p = 0.349). In summary, ACE2 expression increases with age in the setting of alveolar damage observed in patients on mechanical ventilation, providing a potential mechanism for higher Covid-19 mortality in the elderly.

Further comments on the role of ACE‐2 positive macrophages in human lung

“…There were inconsistent results regarding the ACE2 mRNA expression in alveolar macrophages reported by RNA‐seq analysis. Contrasted with the reports [ 14 , 15 , 16 ], the ACE2 mRNA expression in alveolar macrophages were indicated by other groups [ 5 , 11 , 13 ]. In agreement with these studies, our current studies have demonstrated ACE2 protein expression on alveolar, lipopolysaccharide (LPS)‐treated and other tissue macrophages [ 1 ].…”

“…The ACE2 expression on the surface of macrophages have been well established by studies such as ACE2 on alveolar macrophages [ 2 , 3 , 4 , 5 , 6 ], blood monocyte‐derived macrophages [ 7 , 8 , 9 ], and macrophages of atherosclerotic carotid arteries [ 10 ]. Specifically, the ACE2 protein expression on alveolar macrophages has been demonstrated by different studies with lung tissues from normal human and COVID‐19 patients (Table 1 ).…”

Pneumocytes are distinguished by highly elevated expression of the ER stress biomarker GRP78, a co-receptor for SARS-CoV-2, in COVID-19 autopsies

“…In support of this notion, a humanized monoclonal antibody to GRP78 was recently shown to not only reduce cell surface ACE2 but to decrease SARS-CoV-2 entry and infection (Carlos et al, 2021 ). ACE2 expression is reported to increase with age in patients requiring mechanical ventilation (Baker et al, 2021 ), raising the additional possibility that mechanical ventilation may contribute to the observed increased GRP78 levels in pneumocytes via enhanced ACE2 in the autopsied COVID-19 lungs. However, age-related increase in ACE2 expression from mechanical ventilation alone cannot account for our observations because increased GRP78 scores in pneumocytes and macrophages were observed across all age groups with COVID-19, without a relationship to age.…”

Interleukin-6 Perpetrator of the COVID-19 Cytokine Storm

“…Age is another risk factor for poorer prognosis in COVID-19 [ 53 ]. This age-associated vulnerability is probably due to increased expression of ACE2 with age accounting for higher mortality in elderly patients [ 64 ].…”