Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies.
Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies.
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Regadenoson用于治疗COVID-19：五例临床系列和小鼠研究。
DOI：
10.1371/journal.pone.0288920
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
腺苷抑制大多数免疫细胞和血小板的激活。选择性腺苷A2A受体（A2AR）激动剂，如regadenoson (RA)，主要通过抑制不变性自然杀伤T （iNKT）细胞的激活，减少大多数组织的炎症，包括缺氧、缺血、移植或镰状细胞性贫血损伤的肺。RA的抗炎作用在损伤组织中被放大，这是由于免疫细胞中诱导了A2ARs和胞外空间将ATP转化为腺苷的外切酶CD39和CD73。在这里，我们描述了一项五名患者的研究结果，该研究旨在评估RA的安全性，并寻求住院COVID-19患者细胞因子风暴减少的证据。5例需补氧但未插管的COVID-19患者（WHO分期4 ~ 5期）静脉注射RA负荷剂量5 μg/kg/h，持续0.5 h，维持剂量1.44 μg/kg/h，持续6 h，记录生命体征和动脉血氧饱和度，并在RA输注前、输注中、输注后采集血样，分析CRP、d -二聚体、循环iNKT细胞活化状态和血浆13种促炎因子水平。RA无严重副作用，在开始输注后24小时内血氧饱和度升高（93.8±0.58 vs 96.6±1.08%，P<0.05）， d -二聚体降低（754±17 vs 518±98 ng/ml， P<0.05）， CRP降低趋势（3.80±1.40 vs 1.98±0.74 mg/dL, P = 0.075）。循环iNKT细胞，而不是常规T细胞，在COVID-19患者中高度活化（65% vs 5% CD69+）。RA输注30min可使iNKT细胞活化率降低50% （P<0.01）。RA输注30分钟不影响血浆细胞因子，但输注4.5或24小时可降低13种促炎细胞因子中11种的水平。在单独的小鼠研究中，Alzet微型泵以1.44 μg/kg/h皮下输注RA使感染sars - cov -2的K18-hACE2小鼠的10天存活率从10%提高到40% （P<0.001）。输注RA是安全的，并产生快速的抗炎作用，由A2A腺苷受体对iNKT细胞介导，可能部分由A2ARs对其他免疫细胞和血小板介导。我们推测iNKT细胞是通过释放损伤诱导的糖脂抗原和/或来自病毒感染的II型上皮细胞的IL-33等警报器而激活的，这些警报器反过来激活iNKT细胞和其他免疫细胞。从缺氧组织中释放的腺苷，或作为抗炎剂注入的RA，可减少促炎细胞因子，可能有助于治疗Covid-19或其他炎症性肺部疾病或创伤患者的细胞因子风暴。
Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppressing the activation of invariant natural killer T (iNKT) cells. The anti-inflammatory effects of RA are magnified in injured tissues due to induction in immune cells of A2ARs and ecto-enzymes CD39 and CD73 that convert ATP to adenosine in the extracellular space. Here we describe the results of a five patient study designed to evaluate RA safety and to seek evidence of reduced cytokine storm in hospitalized COVID-19 patients. Five COVID-19 patients requiring supplemental oxygen but not intubation (WHO stages 4–5) were infused IV with a loading RA dose of 5 μg/kg/h for 0.5 h followed by a maintenance dose of 1.44 μg/kg/h for 6 hours, Vital signs and arterial oxygen saturation were recorded, and blood samples were collected before, during and after RA infusion for analysis of CRP, D-dimer, circulating iNKT cell activation state and plasma levels of 13 proinflammatory cytokines. RA was devoid of serious side effects, and within 24 hours from the start of infusion was associated with increased oxygen saturation (93.8 ± 0.58 vs 96.6 ± 1.08%, P<0.05), decreased D-dimer (754 ± 17 vs 518 ± 98 ng/ml, P<0.05), and a trend toward decreased CRP (3.80 ± 1.40 vs 1.98 ± 0.74 mg/dL, P = 0.075). Circulating iNKT cells, but not conventional T cells, were highly activated in COVID-19 patients (65% vs 5% CD69+). RA infusion for 30 minutes reduced iNKT cell activation by 50% (P<0.01). RA infusion for 30 minutes did not influence plasma cytokines, but infusion for 4.5 or 24 hours reduced levels of 11 of 13 proinflammatory cytokines. In separate mouse studies, subcutaneous RA infusion from Alzet minipumps at 1.44 μg/kg/h increased 10-day survival of SARS-CoV-2-infected K18-hACE2 mice from 10 to 40% (P<0.001). Infused RA is safe and produces rapid anti-inflammatory effects mediated by A2A adenosine receptors on iNKT cells and possibly in part by A2ARs on other immune cells and platelets. We speculate that iNKT cells are activated by release of injury-induced glycolipid antigens and/or alarmins such as IL-33 derived from virally infected type II epithelial cells which in turn activate iNKT cells and secondarily other immune cells. Adenosine released from hypoxic tissues, or RA infused as an anti-inflammatory agent decrease proinflammatory cytokines and may be useful for treating cytokine storm in patients with Covid-19 or other inflammatory lung diseases or trauma.
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影响因子：
3.7
作者：
Correale P;Caracciolo M;Bilotta F;Conte M;Cuzzola M;Falcone C;Mangano C;Falzea AC;Iuliano E;Morabito A;Foti G;Armentano A;Caraglia M;De Lorenzo A;Sitkovsky M;Macheda S
通讯作者：
Macheda S
DOI：
10.1016/j.jaci.2020.11.006
发表时间：
2021-03
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Bozzi G;Mangioni D;Minoia F;Aliberti S;Grasselli G;Barbetta L;Castelli V;Palomba E;Alagna L;Lombardi A;Ungaro R;Agostoni C;Baldini M;Blasi F;Cesari M;Costantino G;Fracanzani AL;Montano N;Monzani V;Pesenti A;Peyvandi F;Sottocorno M;Muscatello A;Filocamo G;Gori A;Bandera A
通讯作者：
Bandera A
DOI：
10.1084/jem.20061097
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lappas CM;Day YJ;Marshall MA;Engelhard VH;Linden J
通讯作者：
Linden J
影响因子：
5.4
作者：
McCray, Paul B., Jr.;Pewe, Lecia;Perlman, Stanley
通讯作者：
Perlman, Stanley
影响因子：
15.9
作者：
Chen, Guang;Wu, Di;Ning, Qin
通讯作者：
Ning, Qin