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.

项目摘要/摘要 SARS-COV2需要血管紧张素转换酶2（ACE2）与宿主鼻皮细胞结合。 但是，在SARS-COV与ACE2结合后，内部化会导致ACE2活性降低。 ACE2可以 产生具有生物活性肽（ANG（1-9）和ANG（1-7）），它们可抵抗严重的COVID-19-- 诱发肺损伤。因此，尽管鼻上皮中的ACE2表达是病毒的必需点 一旦患者感染，感染，持续的高水平的ACE2活性可能会在矛盾的情况下提供益处。这 调节ACE2表达和活动的宿主因素尚不清楚，并且需要缺少零件 扩展我们对这种疾病发病机理的理解。 2020年3月，一位法国卫生部长建议NSAID使用可能与更严重的 Covid-19患者的疾病表现。现在有一个拼命的尝试来了解是否 NSAID的使用仅与呼吸结局恶化或实际原因相关。如发烧和 Myalgias与Covid-19有关，并且两者通常都被NSAID进行推定对待，这是当务之急 我们了解NSAID在该疾病中的免疫学影响。 对于更严重的199与19与呼吸相关的潜力，也有相当大的关注 2型炎症患者的疾病，以及阿司匹林诊断呼吸道的患者子集 疾病（AERD）在窦的解剖区域中有严重的上呼吸道炎症 发现ACE2表达最高的地方。尚不知道慢性的存在 2型呼吸道炎症会影响呼吸道或血液中的ACE2水平。 我们已经收集了鼻皮细胞（用于ACE2表达的mRNA评估），并且两种鼻液 以及血清和血浆（用于上述血管紧张素衍生肽的ELISA测量） 存放，可立即进行分析。有了这些，我们旨在阐明两个问题 困扰Covid-19患者的评估和治疗： 1）使用NSAIDS是否会增加Covid-19的严重并发症的风险？ 2）患有哮喘和2型呼吸道炎症患者，严重风险增加 COVID-19的并发症？ 这些目标的完成将使我们能够就NSAID使用的安全性提出建议 新冠肺炎。许多患者目前正在选择停止定期开处方的阿司匹林和NSAID脱离 恐惧，我们怀疑这是没有根据的。我们还将进一步了解患有严重2型的患者是否 与呼吸道炎症相比 健康的对照，这表明这些患者的严重COVID风险不同。