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.

项目概要/摘要 SARS-CoV2 需要血管紧张素转换酶 2 (ACE2) 才能与宿主鼻上皮细胞结合。 然而，SARS-CoV 与 ACE2 结合后，内化会导致 ACE2 活性降低。 ACE2可以 产生生物活性肽（Ang(1-9) 和 Ang(1-7)），可预防严重的 COVID-19- 诱发肺损伤。因此，尽管鼻上皮中的ACE2表达是病毒的必需进入点 然而，一旦患者被感染，持续高水平的 ACE2 活性可能反而会带来益处。这 调节 ACE2 表达和活性的宿主因子尚不完全清楚，并且缺少调节 ACE2 表达和活性所需的片段。 扩大我们对该疾病发病机制的了解。 2020 年 3 月，法国卫生部长表示，使用 NSAID 可能会导致更严重的症状 COVID-19 患者的疾病表现。现在正在拼命尝试了解是否 非甾体抗炎药的使用与呼吸系统恶化仅相关，或者实际上是呼吸系统恶化的原因。由于发烧和 肌痛与新冠肺炎 (COVID-19) 相关，并且两者通常都需要使用非甾体抗炎药 (NSAID) 进行治疗，因此势在必行 我们了解非甾体抗炎药在这种疾病中的免疫学影响。 人们还非常担心可能出现更严重的 COVID-19 相关呼吸道疾病 患有 2 型炎症的患者以及阿司匹林加剧呼吸道疾病的患者亚群 疾病（AERD）在鼻窦解剖区域有严重的上呼吸道炎症 其中 ACE2 表达量最高。目前尚不清楚慢性病的存在是如何发生的 2 型驱动的呼吸道炎症会影响呼吸道或血液中的 ACE2 水平。 我们收集了鼻上皮细胞（用于 ACE2 表达的 mRNA 评估），以及鼻液 以及血清和血浆（用于上述血管紧张素衍生肽的 ELISA 测量） 已存入银行并可供立即分析。通过这些，我们的目的是阐明两个问题： 困扰着 COVID-19 患者的评估和治疗： 1) 使用 NSAID 是否会增加 COVID-19 严重并发症的风险？ 2) 患有哮喘和 2 型呼吸道炎症的患者发生严重重症的风险是否增加？ COVID-19 引起的并发症？ 完成这些目标将使我们能够就 NSAID 使用的安全性提出建议 新冠肺炎。许多患者目前选择停止服用常规处方的阿司匹林和非甾体抗炎药。 恐惧，我们怀疑这是没有根据的。我们还将进一步了解重症2型患者是否 与其他呼吸道炎症相比，呼吸道炎症具有不同的鼻腔 ACE2 表达和血管紧张素肽水平 健康对照，这表明这些患者患重症 COVID-19 的风险不同。