Department of Pharmaceutical Sciences, St. John's University, Queens, NY, USA.
School of Medicine, Tulane University, New Orleans, LA, USA.
J Immunotoxicol. 2021 Dec;18(1):23-29. doi: 10.1080/1547691X.2021.1875085.
The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury (ALI). In contrast, acute respiratory distress syndrome (ARDS) and respiratory failure occur in patients diagnosed with severe COVID-19. ARDS is mediated, at least in part, by a dysregulated inflammatory response due to excessive levels of circulating cytokines, a condition known as the "cytokine-storm syndrome." Currently, there are FDA-approved therapies that attenuate the dysregulated inflammation that occurs in COVID-19 patients, such as dexamethasone or other corticosteroids and IL-6 inhibitors, including sarilumab, tocilizumab, and siltuximab. However, the efficacy of these treatments have been shown to be inconsistent. Compounds that activate the vagus nerve-mediated cholinergic anti-inflammatory reflex, such as the α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuate ARDS/inflammatory lung injury by decreasing the extracellular levels of high mobility group box-1 (HMGB1) in the airways and the circulation. It is possible that HMGB1 may be an important mediator of the "cytokine-storm syndrome." Notably, high plasma levels of HMGB1 have been reported in patients diagnosed with severe COVID-19, and there is a significant negative correlation between HMGB1 plasma levels and clinical outcomes. Nicotine can activate the cholinergic anti-inflammatory reflex, which attenuates the up-regulation and the excessive release of pro-inflammatory cytokines/chemokines. Therefore, we hypothesize that low molecular weight compounds that activate the cholinergic anti-inflammatory reflex, such as nicotine or GTS-21, may represent a potential therapeutic approach to attenuate the dysregulated inflammatory responses in patients with severe COVID-19.
2019 年的冠状病毒 SARS-CoV-2（COVID-19）引发了一场大流行，已在全球范围内诊断出超过 7000 万人感染。COVID-19 的轻症至中度症状包括咳嗽、发热、肌肉疼痛、呼吸急促和急性炎症性肺损伤（ALI）。相比之下，严重 COVID-19 患者会出现急性呼吸窘迫综合征（ARDS）和呼吸衰竭。ARDS 至少部分是由于循环细胞因子水平过高引起的失调性炎症反应介导的，这种情况被称为“细胞因子风暴综合征”。目前，有 FDA 批准的疗法可减轻 COVID-19 患者发生的失调性炎症，例如地塞米松或其他皮质类固醇和 IL-6 抑制剂，包括 sarilumab、tocilizumab 和 siltuximab。然而，这些治疗方法的疗效并不一致。激活迷走神经介导的胆碱能抗炎反射的化合物，如α7 烟碱型乙酰胆碱受体激动剂 GTS-21，通过降低气道和循环中高迁移率族蛋白 1（HMGB1）的细胞外水平，减轻 ARDS/炎症性肺损伤。HMGB1 可能是“细胞因子风暴综合征”的重要介质。值得注意的是，严重 COVID-19 患者的血浆中 HMGB1 水平较高，并且 HMGB1 血浆水平与临床结局之间存在显著负相关。尼古丁可以激活胆碱能抗炎反射，从而减轻促炎细胞因子/趋化因子的上调和过度释放。因此，我们假设激活胆碱能抗炎反射的低分子量化合物，如尼古丁或 GTS-21，可能代表一种减轻严重 COVID-19 患者失调性炎症反应的潜在治疗方法。
