Institute of Immunological and Physiopathological Studies, Faculty of Exact Sciences, National University of La Plata, CONICET, Asociated to CIC PBA, La Plata City, Buenos Aires, Argentina.
Institute of Biomedical Research in Retroviruses and AIDS, School of Medicine, University of Buenos Aires, CONICET, Buenos Aires City, Argentina.
Biomed J. 2023 Feb;46(1):81-92. doi: 10.1016/j.bj.2022.07.008. Epub 2022 Aug 7.
Severe cases of Coronavirus Disease 2019 (COVID-19) that require admission to the Intensive Care Unit (ICU) and mechanical ventilation assistance show a high mortality rate with currently few therapeutic options available. Severe COVID-19 is characterized by a systemic inflammatory condition, also called "cytokine storm", which can lead to various multi-organ complications and ultimately death. Lidocaine, a safe local anesthetic that given intravenously is used to treat arrhythmias, has long been reported to have an anti-inflammatory and pro-homeostatic activity.
We studied the capacity of lidocaine to modulate cytokine secretion of mouse and human myeloid cell lines activated by different cytokines or Toll Like Receptor (TLR) ligands (flagellin (FliC), Lipopolysaccharide (LPS), Polyinosinic:polycytidylic acid (Poly I:C) and N-Palmitoyl-S- [2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteinyl-(S)-seryl-(S)-lysyl-(S)-lysyl-(S)-lysyl-(S)-lysine x 3HCl (Pam3Cys-SKKKK)) or by Severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection to epithelial cells. Reporter cell lines were used to study modulation of lidocaine of specific signaling pathways.
Lidocaine used in combination with dexamethasone, had an additive effect in the modulation of cellular inflammatory response triggered by Tumoral Necrosis Factor alpha (TNFα), Interleukin 1 beta (IL-1β) as well as different TLR ligands. We also found that lidocaine in combination with dexamethasone modulates the Nuclear factor kappa B (NF-κB) pathway, inflammasome activation as well as interferon gamma receptor (IFNγR) signaling without affecting the type I interferons (Type I IFNs) pathway. Furthermore, we showed that lidocaine and dexamethasone treatment of epithelial cells infected with SARS-CoV-2 modulated the expression of chemokines that contribute to pro-inflammatory effects in severe COVID.
We reported for the first time in vitro anti-inflammatory capacity of lidocaine on SARS-CoV-2 triggered immune pathways. These results indicated the potential of lidocaine to treat COVID-19 patients and add tools to the therapeutic options available for these concerning cases.
需要入住重症监护病房（ICU）并接受机械通气辅助的 2019 年冠状病毒病（COVID-19）重症病例死亡率较高，目前治疗选择有限。COVID-19 重症的特征是全身性炎症状态，也称为“细胞因子风暴”，可导致各种多器官并发症，并最终导致死亡。利多卡因是一种安全的局部麻醉剂，静脉内给药用于治疗心律失常，长期以来一直被报道具有抗炎和促进体内平衡的作用。
我们研究了利多卡因调节由不同细胞因子或 Toll 样受体（TLR）配体（鞭毛蛋白（FliC）、脂多糖（LPS）、多聚肌苷酸：多聚胞苷酸（Poly I:C）和 N-棕榈酰-S- [2,3-双（棕榈酰氧基）-（2RS）-丙基]-（R）-半胱氨酸-（S）-丝氨酸-（S）-赖氨酸-（S）-赖氨酸-（S）-赖氨酸-（S）-赖氨酸-3HCl（Pam3Cys-SKKKK））或严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染上皮细胞的小鼠和人髓样细胞系细胞因子分泌的能力。报告细胞系用于研究利多卡因对特定信号通路的调节作用。
利多卡因与地塞米松联合使用，可增强肿瘤坏死因子α（TNFα）、白细胞介素 1β（IL-1β）以及不同 TLR 配体引发的细胞炎症反应的调节作用。我们还发现，利多卡因与地塞米松联合调节核因子 kappa B（NF-κB）途径、炎症小体激活以及干扰素γ受体（IFNγR）信号，而不影响 I 型干扰素（Type I IFNs）途径。此外，我们表明利多卡因和地塞米松治疗感染 SARS-CoV-2 的上皮细胞可调节趋化因子的表达，这些趋化因子有助于严重 COVID 中的促炎作用。
我们首次在体外报告了利多卡因对 SARS-CoV-2 触发的免疫途径的抗炎作用。这些结果表明利多卡因治疗 COVID-19 患者的潜力，并为这些令人关注的病例提供了更多的治疗选择。
