<scp>ACE2</scp> expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma

Wark, Peter; Pathinayake, Prabuddha S; Kaiko, Gerard E.; Nichol, Kristy S; Ali, Ayesha; Ling, Chen; Sutanto, Erika N.; Garratt, Luke W.; Sohal, Sukhwinder Singh; Lu, Wenying; Eapen, Mathew Suji; Oldmeadow, Christopher; Bartlett, Nathan W.; Reid, Andrew T; Veerati, Punnam Chander; Hsu, Alan; Looi, Kevin; Iosifidis, Thomas; Stick, Stephen M.; Hansbro, Philip M.; Kicic, Anthony

doi:10.1111/resp.14003

Cited by 60 publications

(58 citation statements)

References 49 publications

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“…For example, in nasal epithelium, a critical site of SARS-CoV-2 entry, ACE2 gene expression increases with age [ 143 ]. Similarly, a recent study found ACE2 gene expression in airway epithelial cells higher in older male patients, even as its expression pattern varied in other organs and in women [ 144 , 145 ]. Lastly, sACE2 levels are elevated in numerous high-risk groups [ 43 , 44 , 146 ].…”

Section: Evidence For Ace2 Downregulation Modelmentioning

confidence: 93%

Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19

Cook

Ausiello

2021

Rev Endocr Metab Disord

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SARS-CoV-2, the virus responsible for COVID-19, uses angiotensin converting enzyme 2 (ACE2) as its primary cell-surface receptor. ACE2 is a key enzyme in the counter-regulatory pathway of the broader renin-angiotensin system (RAS) that has been implicated in a broad array of human pathology. The RAS is composed of two competing pathways that work in opposition to each other: the “conventional” arm involving angiotensin converting enzyme (ACE) generating angiotensin-2 and the more recently identified ACE2 pathway that generates angiotensin (1–7). Following the original SARS pandemic, additional studies suggested that coronaviral binding to ACE2 resulted in downregulation of the membrane-bound enzyme. Given the similarities between the two viruses, many have posited a similar process with SARS-CoV-2. Proponents of this ACE2 deficiency model argue that downregulation of ACE2 limits its enzymatic function, thereby skewing the delicate balance between the two competing arms of the RAS. In this review we critically examine this model. The available data remain incomplete but are consistent with the possibility that the broad multisystem dysfunction of COVID-19 is due in large part to functional ACE2 deficiency leading to angiotensin imbalance with consequent immune dysregulation and endothelial cell dysfunction.

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Section: Evidence For Ace2 Downregulation Modelmentioning

confidence: 93%

Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19

Cook

Ausiello

2021

Rev Endocr Metab Disord

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“…A previous study has also found decreased ACE2 expression in a rat model of COPD exposed to cigarette smoke [75] . In another study, ACE2 expression in the airway epithelium was lower in asthmatic patients but not significantly different between COPD patients and healthy controls [76] . Therefore, the evidence is still conflicting regarding the impact of COPD and smoking on the cellular ACE2 expression.…”

Section: Introductionmentioning

confidence: 90%

Diseased lungs may hinder COVID-19 development: A possible reason for the low prevalence of COPD in COVID-19 patients

Yong

2021

Medical Hypotheses

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Presently, it remains unclear why the prevalence of lung diseases, namely chronic obstructive pulmonary disease (COPD), is much lower than other medical comorbidities and the general population among patients with coronavirus disease 2019 (COVID-19). If COVID-19 is a respiratory disease, why is COPD not the leading risk factor for contracting COVID-19? The same odd phenomenon was also observed with other pathogenic human coronaviruses causing severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS), but not other respiratory viral infections such as influenza and respiratory syncytial viruses. One commonly proposed reason for the low COPD rates among COVID-19 patients is the usage of inhaled corticosteroids or bronchodilators that may protect against COVID-19. However, another possible reason not discussed elsewhere is that lungs in a diseased state may not be conducive for the severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) to establish COVID-19. For one, COPD causes mucous plugging in large and small airways, which may hinder SARS-CoV-2 from reaching deeper parts of the lungs (i.e., alveoli). Thus, SARS-CoV-2 may only localize to the upper respiratory tract of persons with COPD, causing mild or asymptomatic infections requiring no hospital attention. Even if SARS-CoV-2 reaches the alveoli, cells therein are probably under a heavy burden of endoplasmic reticulum (ER) stress and extensively damaged where it may not support efficient viral replication. As a result, limited SARS-CoV-2 virions would be produced in diseased lungs, preventing the development of COVID-19.

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“…RNA sequencing of upper and lower airway cells from three different cohorts including children and adults identified asthma and respiratory allergies to be associated with significantly reduced ACE2 expression ( 43 ). Age and male sex are known risk factors for COVID-19 and accordingly, increased expression of ACE2 was noted in the airways of older population and males ( 44 ). In patients with asthma, the reduced gene and protein expression of ACE2 was accompanied by lower expression of furin, a protease that cleaves the spike glycoprotein, and higher expression of ADAM-17 , a disintegrin that cleaves ACE2 from the surface ( 44 ).…”

Section: Implications Of Asthma Pathobiology On Covid-19 Pathogenesismentioning

confidence: 99%

“…Age and male sex are known risk factors for COVID-19 and accordingly, increased expression of ACE2 was noted in the airways of older population and males ( 44 ). In patients with asthma, the reduced gene and protein expression of ACE2 was accompanied by lower expression of furin, a protease that cleaves the spike glycoprotein, and higher expression of ADAM-17 , a disintegrin that cleaves ACE2 from the surface ( 44 ). COVID-19 patients with asthma were also characterized by a reduction in ACE2 protein expression in their lower airways, when compared with COVID-19 subjects without asthma ( 45 ).…”

Section: Implications Of Asthma Pathobiology On Covid-19 Pathogenesismentioning

confidence: 99%

Implications of preexisting asthma on COVID-19 pathogenesis

Ramakrishnan

Heialy

Hamid

2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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The coronavirus disease 2019 (COVID-19) pandemic spreading at an alarming rate has taken a heavy toll on the public healthcare systems and economies worldwide. An abnormal and overactivated inflammatory response is occasionally elicited by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and this hyperinflammation is associated with worse prognosis of COVID-19. Theoretically, one would expect asthma patients to be at a greater risk of SARS-CoV-2 infection considering their increased susceptibility to common respiratory virus-associated exacerbations. Surprisingly, current data do not consistently suggest an increased prevalence of asthma among COVID-19 patients. Considering the high global prevalence of asthma, the characteristics of the disease and/or their conventional therapy might play a role in their potential defense against COVID-19. This may be attributed to the T helper type 2 immune response predominantly seen in asthmatics. Likewise, asthma therapeutics, including corticosteroids and biologics, may in fact benefit the asthmatics by alleviating the development of hyperinflammation. On the other hand, elevated IL-17 levels are characteristically seen in a subset of asthma patients with severe disease as well as in COVID-19 patients. Targeting the IL-17 pathway as a treatment strategy could plausibly alleviate acute respiratory distress syndrome (ARDS) in COVID-19 patients with asthma demonstrating a predominant T helper type 17 response. A clinical trial including a drug targeting this pathway may thus, constitute a logical addition to the global pursuit for effective therapeutics against COVID-19. The complex interplay between the asthma endotypes and COVID-19 is not very well understood and will be discussed in this mini-review.

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ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma

Cited by 60 publications

References 49 publications

Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19

Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19

Diseased lungs may hinder COVID-19 development: A possible reason for the low prevalence of COPD in COVID-19 patients

Implications of preexisting asthma on COVID-19 pathogenesis

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