蛋白酶体抑制剂抑制危重期COVID-19患者细胞因子风暴的潜力
Potential of proteasome inhibitors to inhibit cytokine storm in critical stage COVID-19 patients
摘要：
感染SARS-CoV-2的患者表现出广泛的临床表现，从轻度发热和咳嗽到急性呼吸窘迫综合征、多器官衰竭和死亡。与具有轻度症状的患者相比，来自具有严重临床表现的患者的数据表明，高度失调的旺盛的炎症反应与疾病的严重程度和致死性相关。显著升高的细胞因子水平，即细胞因子风暴，似乎在COVID-19的严重性和致死性中起着核心作用。我们以前已经表明，过度的细胞因子释放诱导的高致病性禽流感病毒H5 N1 A型，减少了蛋白酶体抑制剂的应用。在本研究中，我们在已发表的COVID-19患者临床数据的背景下，提供了中央细胞促炎信号通路NF-κ B的实验数据，并提出了一种治疗方法的假设，旨在通过蛋白酶体抑制剂阻断NF-κ B的核转位，同时抑制促炎细胞因子和趋化因子的整个级联反应。与单一靶点方法相比，使用临床批准的蛋白酶体抑制剂同时抑制多种细胞因子/趋化因子预期具有更高的治疗潜力，以防止多种诱导细胞因子的级联（即触发、协同和冗余）效应，并可能为治疗危重期COVID-19患者提供额外的治疗选择。
英文摘要：
Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Significantly elevated cytokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. We have previously shown that excessive cytokine release induced by highly pathogenic avian H5N1 influenza A virus was reduced by application of proteasome inhibitors. In the present study we present experimental data of a central cellular pro-inflammatory signal pathways, NF-kappaB, in the context of published clinical data from COVID-19 patients and develop a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines via blocking the nuclear translocation of NF-kappaB by proteasome inhibitors. The simultaneous inhibition of multiple cytokines/chemokines using clinically approved proteasome inhibitors is expected to have a higher therapeutic potential compared to single target approaches to prevent cascade (i.e. triggering, synergistic, and redundant) effects of multiple induced cytokines and may provide an additional therapeutic option to be explored for treatment of critical stage COVID-19 patients.
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