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Background Angiotensin-converting enzyme 2 (ACE2) is the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19. Viral entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). Transcriptomic studies showed that children display lower ACE2 than adults, though gene expression levels do not always correlate with protein levels. We investigated the effect of age on ACE2 and TMPRSS2 protein expression in alveolar type II (AT2) cells in the lungs of children compared to adults. We also analysed the ratio of Ang-(1–7) to Ang II as a surrogate marker of ACE2 activity in the subjects’ lung parenchyma. Methods Ang II and Ang-(1–7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. Results The amount of ACE2-expressing AT2 cells and ACE2 protein content were lower in children than in adults. Ang II levels were higher in children compared to adults and inversely correlated with the amount of ACE2-expressing AT2 cells. Children presented lower Ang-(1–7)/Ang II ratio than adult suggesting lower ACE2 activity in children. TMPRSS2 protein expression was not influenced by age. Conclusions These results expand on previous transcriptomic studies and may partially explain the low susceptibility of children to SARS-CoV-2 infection. Category of study Clinical original research Impact Children display lower ACE2 protein content and activity compared to adults. Ang II levels were higher in children compared to adults and inversely correlated with the amount of ACE2-expressing AT2 cells TMPRSS2 protein expression was not influenced by age. These results expand on previous transcriptomic studies and may partially explain the low susceptibility of children to SARS-CoV-2 infection.

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Aims Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. Main methods Ang II and Ang-(1–7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. Key findings We found that the ratio Ang-(1–7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. Significance ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies.

Aims. In addition to its enzymatic function counterbalancing the pressor arm of the renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE) 2 acts as the receptor for SARS-CoV-2. Viral fusion and cellular entry require ACE2 and the transmembrane protease serine 2 (TMPRSS2). Some evidence in tissue animals showed that RAS blockade by either ACE inhibitors (ACEIs) or type 1 angiotensin receptor blockers (ARBs) influence ACE2, though evidence in human lungs is lacking. Our aim was to evaluate ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, present in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. Methods and Results. ACE2 and TMPRSS2 protein expression was evaluated by immunohistochemistry. The percentage of ACE2-expressing type II pneumocytes were not different between male and female. We found a significant interaction between ACEI/ARB treatment and smoking on ACE2-expressing type II pneumocytes (P = 0.026). Subjects with a positive history of smoking and ACEI/ARB treatment contained higher number of ACE2-expressing type II pneumocytes. Furthermore, ACE2 protein content correlated positively with smoking habits and age (P = 0.05). On the other hand, the percentage of TMPRSS2-expressing type II pneumocytes were higher in males than females (P = 0.026) and in subjects under 60 years of age (P = 0.04) and not significantly influenced by ACEI/ARB treatment (p=0.06). There was a positive association of TMPRSS2 protein content with age (P = 0.001) and smoking (P = 0.039) in ACEI/ARB-treated subjects with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. Conclusions. We conclude that ACEI/ARB treatment influences human lung ACE2 and TMPRSS2 but this effect depends on the age and smoking habits of the subject.