Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells.
Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells.
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DOI：
10.3389/fphar.2021.765951
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发表时间：
2021
影响因子：
5.6
通讯作者：
Debley JS
中科院分区：
文献类型：
--
作者：
Okoloko O;Vanderwall ER;Rich LM;White MP;Reeves SR;Harrington WE;Barrow KA;Debley JS
理由：SARS-CoV-2 通过病毒刺突蛋白与细胞表面的血管紧张素转换酶 2 (ACE2) 结合而进入气道上皮细胞 (AEC)。然而，ACE2 还可将血管紧张素 II 转化为血管紧张素-(1-7)，并平衡肾素-血管紧张素-醛固酮系统，从而对心血管系统产生保护作用。一些数据表明，两种常见的抗高血压药物（血管紧张素 II 受体拮抗剂，ARB 和血管紧张素转换酶抑制剂，ACEIs）可能会增加心脏和肾脏细胞中 ACE2 的表达，引发了关于这些广泛使用的药物如何调节 SARS-CoV-2 感染性和 COVID-19 风险的争论。 目的：确定支气管 AEC 暴露于 ARB 氯沙坦或 ACEI 卡托普利是否会通过 AEC、SARS CoV2 复制或促炎细胞因子的表达以及 I 型和 III 型干扰素 (IFN) 反应调节 ACE2 的表达。 方法：将儿童和成人（n = 19；年龄 8-75 岁）的原发性支气管 AEC 在气液界面进行离体分化，以产生器官型培养物。用卡托普利 (1 μM) 或氯沙坦 (2 μM) 处理培养物，并在感染 SARS-CoV-2 前 72 小时开始更换培养基。在生物安全 3 级 (BSL-3) 设施中，培养物感染了 SARS-CoV-2 分离株 USA-WA1/2020，感染复数 (MOI) 为 0.5。感染后 96 小时，分离出 RNA 和蛋白质。使用定量 PCR (qPCR) 评估培养物中的 SARS-CoV-2 复制。通过 qPCR 评估 ACE2、IL-6、IL-1B、IFNB1 和 IFNL2 表达。 结果：与未经卡托普利或氯沙坦治疗的 SARS-CoV-2 感染 AEC 培养物相比，卡托普利或氯沙坦治疗均未显着改变 AEC 的 ACE2、IL-6、IL-1B、IFNB1 或 IFNL2 表达。感染后 96 小时，未经处理的 AEC 培养物、用卡托普利处理的培养物或用氯沙坦处理的培养物之间，SARS-CoV-2 拷贝数/ng RNA 没有显着差异。 结论：这些研究结果表明，在气道上皮水平，ACEI 卡托普利或 ARB 氯沙坦均未显着改变 SARS-CoV-2 进入因子 ACE2 的表达，这两种药物也不会增加 SARS-CoV-2 的复制。这一离体数据令人放心，并且与不断变化的临床数据一致，表明 ACEI 和 ARB 不会增加 COVID-19 预后不良的风险，实际上可能会降低 COVID-19 疾病的风险。
Rationale: SARS-CoV-2 gains entrance to airway epithelial cells (AECs) through binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) on the cell surface. However, ACE2 also converts angiotensin II into angiotensin-(1-7) and counterbalances the renin-angiotensin-aldosterone system, with resultant protective effects in the cardiovascular system. Some data suggest that two common antihypertension medications (angiotensin II receptor antagonists, ARBs; and angiotensin-converting-enzyme inhibitors, ACEIs) may increase ACE2 expression in heart and kidney cells, fueling debate about how these widely used medications may modulate SARS-CoV-2 infectivity and risk of COVID-19. Aim: Determine whether exposure of bronchial AECs to the ARB losartan or the ACEI captopril modulate expression of ACE2 by AECs, SARS CoV2 replication, or expression of proinflammatory cytokines and type I and III interferon (IFN) responses. Methods: Primary bronchial AECs from children and adults (n = 19; Ages 8–75 yrs) were differentiated ex vivo at an air-liquid interface to generate organotypic cultures. Cultures were treated with captopril (1 μM) or losartan (2 μM) with culture media changes starting 72 h before infection with SARS-CoV-2. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 isolate USA-WA1/2020 at a multiplicity of infection (MOI) of 0.5. At 96 h following infection, RNA and protein were isolated. SARS-CoV-2 replication in cultures was assessed with quantitative PCR (qPCR). ACE2, IL-6, IL-1B, IFNB1, and IFNL2 expression were assessed by qPCR. Results: Neither captopril nor losartan treatment significantly changed ACE2, IL-6, IL-1B, IFNB1, or IFNL2 expression by AECs as compared to SARS-CoV-2 infected AEC cultures without captopril or losartan treatment. At 96 h following infection, SARS-CoV-2 copy number/ng RNA was not significantly different between untreated AEC cultures, cultures treated with captopril, or cultures treated with losartan. Conclusion: These findings suggest that at the level of the airway epithelium neither the ACEI captopril or ARB losartan significantly modify expression of the SARS-CoV-2 entry factor ACE2, nor does either medication increase replication SARS-CoV-2 replication. This ex vivo data is reassuring and is consistent with evolving clinical data suggesting ACEIs and ARBs do not increase the risk for poor prognosis with COVID-19 and may actually reduce the risk of COVID-19 disease.
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影响因子：
14.2
作者：
Lee, Hai-Chon;Headley, Mark B.;Loo, Yueh-Ming;Berlin, Aaron;Gale, Michael, Jr.;Debley, Jason S.;Lukacs, Nicholas W.;Ziegler, Steven F.
通讯作者：
Ziegler, Steven F.
影响因子：
39.2
作者：
Garg, Shikha;Patel, Kadam;Havers, Fiona P.
通讯作者：
Havers, Fiona P.
影响因子：
3.8
作者：
Hastie, AT;Everts, KB;Peters, SP
通讯作者：
Peters, SP
DOI：
10.1038/s41577-021-00553-8
发表时间：
2021-06
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Jones SA;Hunter CA
通讯作者：
Hunter CA
DOI：
10.1016/j.jaci.2011.11.035
发表时间：
2012-04
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Lopez-Guisa JM;Powers C;File D;Cochrane E;Jimenez N;Debley JS
通讯作者：
Debley JS