Yang Huan, George Sam J, Thompson Dane, Silverman Harold A, Tsaava Tea, Tynan Aisling, Pavlov Valentin A, Chang Eric, Andersson Ulf, Brines Michael, Chavan Sangeeta S, Tracey Kevin J
Feinstein Institute for Medical Research.
Feinstein Institute for Medical Research Fertility Research Laboratory: Northwell Health Feinstein Institutes for Medical Research.
Res Sq. 2022 Apr 11:rs.3.rs-1493296. doi: 10.21203/rs.3.rs-1493296/v1.
Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease , attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor ( α7nAChR ) signal transduction, to prevent cytokine storm. The potential anti-inflammatory effects of famotidine and other H2R antagonists was assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor α and interleukin-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.
重症新型冠状病毒肺炎（COVID-19）的特征是促炎性细胞因子释放综合征（细胞因子风暴），这会导致高发病率和死亡率。最近的观察性和临床研究表明，法莫替丁（一种广泛用于治疗胃食管反流病的组胺2受体（H2R）拮抗剂）可减轻COVID-19的临床病程。由于缺乏法莫替丁直接抗病毒活性的证据，其一种可能的作用机制是阻断肥大细胞释放的组胺的作用。在此，我们假设法莫替丁激活炎症反射，这是一种大脑整合的迷走神经机制，通过α7烟碱型乙酰胆碱受体（α7nAChR）信号转导抑制炎症，以预防细胞因子风暴。在暴露于脂多糖（LPS）诱导的细胞因子风暴的小鼠中评估了法莫替丁和其他H2R拮抗剂的潜在抗炎作用。由于炎症反射是整合的且可在大脑中被刺激，并且H2R拮抗剂穿透血脑屏障的能力较差，因此通过脑室内（ICV）或腹腔内（IP）途径给予法莫替丁。腹腔注射法莫替丁可显著降低血清和脾脏中LPS刺激的肿瘤坏死因子α和白细胞介素-6浓度，显著提高存活率。与外周途径相比，脑室内注射法莫替丁的效果显著更强。通过基因缺失缺乏肥大细胞的小鼠也对法莫替丁有反应，表明抗炎作用不依赖于肥大细胞。双侧膈下迷走神经切断术或α7nAChR基因敲除均消除了法莫替丁的抗炎作用，表明炎症反射是法莫替丁的作用机制。虽然结构相似的H2R拮抗剂替奥替丁表现出同等的抗炎活性，但H2R拮抗剂西咪替丁或雷尼替丁即使在非常高的剂量下也无效。这些观察结果揭示了法莫替丁在细胞因子风暴背景下以前未被识别的依赖迷走神经的抗炎作用，而临床使用的其他H2R拮抗剂即使高剂量也无法复制这种作用。由于法莫替丁鞘内给药时更有效，这些发现也与主要的中枢神经系统作用机制一致。
