目的:脓毒症的病理生理学是复杂的,确定脓毒症的有效治疗方法仍然具有挑战性。本研究旨在通过对脓毒症患者的转录组学分析,找出治疗脓毒症的有效药物和靶点。化合物的重新定位分析,并通过动物模型进行验证。
方法:GSE185263从GEO数据库获得,包括44名健康对照和348名按严重程度分类的脓毒症患者的基因表达谱。生物信息学算法揭示了分子,函数,和脓毒症的免疫特征,构建了脓毒症相关蛋白-蛋白相互作用网络。随后,使用Restart分析随机游走来确定败血症的候选药物,在动物模型中进行了生存测试,炎症,凝血,和多器官损伤。
结果:我们的分析发现1862个基因与脓毒症的发展有关,富含中性粒细胞胞外陷阱形成(NETs)和补体/凝血级联等功能。随着疾病进展,免疫激活相关细胞被抑制,而免疫抑制相关细胞被激活。接下来,药物重新定位方法确定了候选药物,如α-1抗胰蛋白酶,可能通过靶向中性粒细胞弹性蛋白酶(NE)抑制NETs来发挥治疗作用。动物实验证明,α-1抗胰蛋白酶治疗可以提高存活率,降低脓毒症评分,降低血清中炎症标志物的水平,减轻脓毒症小鼠多器官形态学损伤。进一步的结果表明,α-1抗胰蛋白酶可以通过抑制NE来抑制NETs,从而治疗脓毒症。
结论:α-1抗胰蛋白酶作用于NE以抑制NETs,从而保护小鼠免于脓毒症诱导的炎症和凝血。
OBJECTIVE: Sepsis pathophysiology is complex and identifying effective treatments for sepsis remains challenging. The study aims to identify effective drugs and targets for sepsis through transcriptomic analysis of sepsis patients, repositioning analysis of compounds, and validation by animal models.
METHODS: GSE185263 obtained from the GEO database that includes gene expression profiles of 44 healthy controls and 348 sepsis patients categorized by severity. Bioinformatic algorithms revealed the molecular, function, and immune characteristics of the sepsis, and constructed sepsis-related protein-protein interaction networks. Subsequently, Random Walk with Restart analysis was applied to identify candidate drugs for sepsis, which were tested in animal models for survival, inflammation, coagulation, and multi-organ damage.
RESULTS: Our analysis found 1862 genes linked to sepsis development, enriched in functions like neutrophil extracellular trap formation (NETs) and complement/coagulation cascades. With disease progression, immune activation-associated cells were inhibited, while immune suppression-associated cells were activated. Next, the drug repositioning method identified candidate drugs, such as alpha-1 antitrypsin, that may play a therapeutic role by targeting neutrophil elastase (NE) to inhibit NETs. Animal experiments proved that alpha-1 antitrypsin treatment can improve the survival rate, reduce sepsis score, reduce the levels of inflammation markers in serum, and alleviate muti-organ morphological damage in mice with sepsis. The further results showed that α-1 antitrypsin can inhibit the NETs by suppressing the NE for the treatment of sepsis.
CONCLUSIONS: Alpha-1 antitrypsin acted on the NE to inhibit NETs thereby protecting mice from sepsis-induced inflammation and coagulation.