Influence of NSAIDs and AERD on the expression and function of ACE2 - implications for SARS-CoV2 severity

NSAID 和 AERD 对 ACE2 表达和功能的影响 - 对 SARS-CoV2 严重程度的影响

• 批准号: 10197400
• 负责人: Joshua A Boyce
• 金额: $ 11.42万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-24 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197400
• 关键词: 2019-nCoV; Affect; Anatomy; Angiotensins; Area; Aspirin; Asthma; Binding; Biological; Blood; COVID-19; Chronic; Clinical Treatment; Clinical assessments; Disease; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Fever; Fright; General Population; Health; Immunologics; Inflammation; Integration Host Factors; Learning; Light; Liquid substance; Lung diseases; Measurement; Messenger RNA; Myalgia; Nasal Epithelium; Non-Steroidal Anti-Inflammatory Agents; Nose; Outcome; Pathogenesis; Patients; Peptides; Peptidyl-Dipeptidase A; Plasma; Recommendation; Respiratory System; Risk; SARS coronavirus; Safety; Serum; Severities; Sinus; Virus Diseases; Work; aspirin-exacerbated respiratory disease; high risk; lung injury; patient subsets; receptor; respiratory

PROJECT SUMMARY/ABSTRACT SARS-CoV2 requires angiotensin-converting enzyme 2 (ACE2) to bind to host nasal epithelial cells. However, upon binding of SARS-CoV to ACE2, internalization leads to decreased ACE2 activity. ACE2 can generate biologically active peptides (Ang(1-9) and Ang(1-7)) which are protective against severe COVID-19- induced lung injury. Therefore, although ACE2 expression in the nasal epithelium is a required entry point for viral infection, continued high levels of ACE2 activity may paradoxically provide benefit once the patient is infected. The host factors that regulate ACE2 expression and activity are not fully known and are missing pieces required to expand our understanding of the pathogenesis of this disease. In March 2020 a French health minister suggested that NSAID use might be associated with more severe disease presentation in patients with COVID-19. There is now a desperate attempt to understand whether NSAID use is simply correlated with, or actually causative of, worsened respiratory outcomes. As fever and myalgias are associated with COVID-19, and both are often treated presumptively with NSAIDs, it is imperative that we understand the immunological influence of NSAIDs in this disease. There is also considerable concern regarding the potential for more severe COVID-19-related respiratory disease in patients with Type 2 inflammation, and the subset of patients with aspirin-exacerbated respiratory disease (AERD) have severe upper respiratory inflammation in exactly the anatomic areas of the sinuses where ACE2 expression has been found to be the highest. It is not yet known how the presence of chronic Type 2-driven respiratory inflammation affects ACE2 levels in the respiratory tract or the blood. We have collected nasal epithelial cells (for mRNA assessment of ACE2 expression), and both nasal fluid and serum and plasma (for ELISA measurement of the angiotensin-derived peptides as above) which are banked and are available for immediate analysis. With these, we aim to shed light on two questions that are plaguing the assessment and treatment of patients with COVID-19: 1) Does use of NSAIDs increase risk of severe complications from COVID-19? 2) Are patients with asthma and Type 2 respiratory inflammation at increased risk of severe complications from COVID-19? Completion of these aims would allow us to make recommendations regarding safety of NSAID use in COVID-19. Many patients are currently choosing to stop their regularly prescribed aspirin and NSAIDs out of fear, which we suspect is unfounded. We will also further understand whether patients with severe Type 2 respiratory inflammation have different nasal ACE2 expression and angiotensin peptide levels, compared to healthy controls, which would suggest a differing risk of severe COVID-19 in those patients.

项目总结/文摘