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Sepsis is a disease responsible for the death of almost all critical patients. Once infected by virus or bacteria, patients can die due to systemic inflammation within a short period of time. Cytokine storm plays an essential role in causing organ dysfunction and septic shock. Thus, inhibition of cytokine secretion is considered very important in sepsis therapy. In this study, we found that TFP, an antipsychotic drug mainly used to treat schizophrenia by suppressing dopamine secretion, inhibited cytokine release from activated immune cells both in vitro and in vivo. Trifluoperazine (TFP) decreased the levels of pro-inflammatory cytokines without altering their transcription level. In LPS-induced endotoxemia and cecal content injection (CCI) models, TFP intraperitoneal administration improved survival rate. Thus, TFP was considered to inhibit the secretion of proteins through a mechanism similar to that of W7, a calmodulin inhibitor. Finally, we confirmed that TFP treatment relieved organ damage by estimating the concentrations of aspartate transaminase (AST), alanine transaminase (ALT), and blood urea nitrogen (BUN) in the serum. Our findings were regarded as a new discovery of the function of TFP in treating sepsis patients. KEY MESSAGES: • TFP inhibits LPS-induced activation of DCs by suppressing pro-inflammatory cytokine. • Treatment of TFP increases survival of LPS-induced endotoxemia and CCI sepsis models. • TFP exerted a protective effect against tissue or organ damage in animal models.

脓毒症是导致几乎所有危重症患者死亡的疾病。一旦病毒或细菌感染，患者可能会在短时间内因全身炎症而死亡。细胞因子风暴在导致器官功能障碍和感染性休克方面起着至关重要的作用。因此，抑制细胞因子的分泌被认为在脓毒症治疗中非常重要。在这项研究中，我们发现，主要通过抑制多巴胺分泌来治疗精神分裂症的抗精神病药物三氟拉嗪（TFP）可抑制激活免疫细胞的细胞因子释放，无论是在体外还是体内。三氟拉嗪（TFP）降低了促炎细胞因子的水平，而不改变其转录水平。在 LPS 诱导的内毒素血症和盲肠内容物注射（CCI）模型中，TFP 腹腔内给药提高了生存率。因此，TFP 被认为通过类似于钙调蛋白抑制剂 W7 的机制抑制蛋白质的分泌。最后，我们通过估计血清中天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）和血尿素氮（BUN）的浓度来确认 TFP 治疗可减轻器官损伤。我们的发现被认为是 TFP 治疗脓毒症患者功能的新发现。