Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm

作者：Huan Yang, Sam J. George, Dane Thompson, Harold Silverman, Téa Tsaava, Aisling Tynan, Valentin A. Pavlov, Eric H. Chang, Ulf Andersson, Michael Brines, Sangeeta S. Chavan, Kevin J. Tracey · 发表于：Molecular Medicine · 年份：2022 · DOI：10.1186/s10020-022-00483-8 · 被引用次数：24 · 研究领域：Vagus Nerve Stimulation Research、Long-Term Effects of COVID-19、Olfactory and Sensory Function Studies

BACKGROUND: 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. METHODS: The potential anti-inflammatory effects of famotidine and other H2R antagonists were 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. RESULTS: Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-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 ...