Xuebijing injection inhibited neutrophil extracellular traps to reverse lung injury in sepsis mice via reducing Gasdermin D.
Xuebijing injection inhibited neutrophil extracellular traps to reverse lung injury in sepsis mice via reducing Gasdermin D.
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DOI：
10.3389/fphar.2022.1054176
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
脓毒症和脓毒性休克的死亡率在世界范围内仍然很高。神经元细胞外陷阱（NETs）释放是脓毒症中器官衰竭和死亡的主要原因。靶向Gasdermin D（GSDMD）可以抑制NETs的形成，这对于脓毒症的治疗是有希望的。然而，没有药物被确定为没有严重的安全性问题，用于此目的。血必净注射液（XBJ）已被证明可以缓解COVID-19和脓毒症患者的临床症状，但还没有足够的动物研究来深入揭示其机制。因此，我们想知道XBJ是否通过抑制NETs形成来减轻脓毒症中的肺损伤，并采用临床相关的多微生物感染模型来验证这一假设。首先，XBJ通过下调促炎趋化因子如CSF-3、CXCL-2和CXCR-2有效地逆转了脓毒症引起的肺损伤并抑制了中性粒细胞向肺的募集。引人注目的是，我们发现XBJ显著降低了NET组分蛋白的表达，包括瓜氨酸化组蛋白H3（CitH 3），髓过氧化物酶（MPO）和中性粒细胞弹性蛋白酶（NE）。GSDMD有助于脓毒症中NET的产生。值得注意的是，XBJ表现出降低GSDMD及其上游调控因子表达的作用。此外，我们还发现XBJ通过抑制GSDMD相关基因的表达来逆转NETs的形成。总的来说，我们证明了XBJ通过逆转GSDMD相关通路来抑制NET的形成，从而保护脓毒症诱导的肺损伤。
The mortality of sepsis and septic shock remains high worldwide. Neutrophil extracellular traps (NETs) release is a major cause of organ failure and mortality in sepsis. Targeting Gasdermin D (GSDMD) can restrain NETs formation, which is promising for sepsis management. However, no medicine is identified without severe safety concerns for this purpose. Xuebijing injection (XBJ) has been demonstrated to alleviate the clinical symptoms of COVID-19 and sepsis patients, but there are not enough animal studies to reveal its mechanisms in depth. Therefore, we wondered whether XBJ relieved pulmonary damage in sepsis by suppressing NETs formation and adopted a clinically relevant polymicrobial infection model to test this hypothesis. Firstly, XBJ effectively reversed lung injury caused by sepsis and restrained neutrophils recruitment to lung by down-regulating proinflammatory chemokines, such as CSF-3, CXCL-2, and CXCR-2. Strikingly, we found that XBJ significantly reduced the expressions of NETs component proteins, including citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase (NE). GSDMD contributes to the production of NETs in sepsis. Notably, XBJ exhibited a reduced effect on the expressions of GSDMD and its upstream regulators. Besides, we also revealed that XBJ reversed NETs formation by inhibiting the expressions of GSDMD-related genes. Collectively, we demonstrated XBJ protected against sepsis-induced lung injury by reversing GSDMD-related pathway to inhibit NETs formation.
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