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

项目摘要/摘要 SARS-CoV2病毒需要血管紧张素转换酶2(ACE2)与宿主鼻上皮细胞结合。 然而，SARS冠状病毒与ACE2结合后，内化导致ACE2活性下降。ACE2可以 产生生物活性多肽(Ang(1-9)和Ang(1-7))，对严重的新冠肺炎具有保护作用 致肺损伤。因此，尽管ACE2在鼻黏膜上皮细胞中的表达是病毒必需的入口点 然而，一旦患者受到感染，持续高水平的ACE2活性可能反而会带来益处。这个 调节ACE2表达和活性的宿主因子尚不完全清楚，并且缺少必要的片段 扩大我们对该病发病机制的认识。 2020年3月，一位法国卫生部长提出，非甾体抗炎药的使用可能与更严重的 新冠肺炎患者的疾病表现。现在，人们不顾一切地试图了解 非甾体抗炎药的使用只是与呼吸结果恶化相关，或者实际上是呼吸结果恶化的原因。就像发烧和 肌痛与新冠肺炎有关，两者都经常被推定为非甾体抗炎药治疗，这是势在必行的 我们了解非类固醇抗炎药在这种疾病中的免疫学影响。 也有相当多的人担心与新冠肺炎相关的更严重的呼吸道疾病的可能性 2型炎症患者和阿司匹林加重呼吸系统患者亚组的疾病 疾病(AERD)在鼻窦的解剖区域有严重的上呼吸道炎症 其中ACE2的表达最高。目前尚不清楚慢性支气管炎的存在如何 2型呼吸道炎症会影响呼吸道或血液中的ACE2水平。 我们收集了鼻腔上皮细胞(用于血管紧张素转换酶2表达的信使核糖核酸的评估)和鼻液 以及血清和血浆(用于上述血管紧张素衍生肽的酶联免疫吸附测定) 存入银行，并可立即进行分析。通过这些，我们的目标是阐明以下两个问题 困扰新冠肺炎患者评估和治疗的是： 1)使用非甾体抗炎药是否会增加新冠肺炎严重并发症的风险？ 2)哮喘和II型呼吸道炎症患者患严重肺炎的风险是否增加 新冠肺炎带来的并发症？ 完成这些目标将使我们能够就#年非甾体抗炎药的使用安全性提出建议。 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 呼吸道炎症有不同的鼻腔ACE2表达和血管紧张素水平，与 健康对照，这表明这些患者严重新冠肺炎的风险不同。

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.