Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a life-threatening syndrome induced by various diseases, including COVID-19. In the progression of ALI/ARDS, activated neutrophils play a central role by releasing various inflammatory mediators, including elastase. Sivelestat is a selective and competitive inhibitor of neutrophil elastase. Although its protective effects on attenuating ALI/ARDS have been confirmed in several models of lung injury, clinical trials have presented inconsistent results on its therapeutic efficacy. Therefore, in this report, we used a network pharmacology approach coupled with animal experimental validation to unravel the concrete therapeutic targets and biological mechanisms of sivelestat in treating ALI/ARDS. In bioinformatic analyses, we found 118 targets of sivelestat against ALI/ARDS, and identified six hub genes essential for sivelestat treatment of ALI/ARDS, namely ERBB2, GRB2, PTK2, PTPN11, ESR1, and CCND1. We also found that sivelestat targeted several genes expressed in human lung microvascular endothelial cells after lipopolysaccharide (LPS) treatment at 4 h (ICAM-1, PTGS2, RND1, BCL2A1, TNF, CA2, and ADORA2A), 8 h (ICAM-1, PTGS2, RND1, BCL2A1, MMP1, BDKRB1 and SLC40A1), and 24 h (ICAM-1). Further animal experiments showed that sivelestat was able to attenuate LPS-induced ALI by inhibiting the overexpression of ICAM-1, VCAM-1, and PTGS2 and increasing the phosphorylation of PTK2. Taken together, the bioinformatic findings and experimentative data indicate that the therapeutic effects of sivelestat against ALI/ARDS mainly focus on the early stage of ALI/ARDS by pharmacological modulation of inflammatory reaction, vascular endothelial injury, and cell apoptosis–related molecules.

中文翻译：

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西维来司他保护急性肺损伤的可能药理学靶点和机制


急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）是一种由多种疾病（包括 COVID-19）引起的危及生命的综合征。在 ALI/ARDS 的进展中，活化的中性粒细胞通过释放各种炎症介质（包括弹性蛋白酶）发挥核心作用。西维来司他是中性粒细胞弹性蛋白酶的选择性和竞争性抑制剂。尽管其减轻 ALI/ARDS 的保护作用已在多种肺损伤模型中得到证实，但临床试验对其治疗效果的结果不一致。因此，在本报告中，我们采用网络药理学方法结合动物实验验证来揭示西维来司他治疗ALI/ARDS的具体治疗靶点和生物学机制。在生物信息学分析中，我们发现了西维来司他治疗ALI/ARDS的118个靶点，并确定了西维来司他治疗ALI/ARDS所必需的6个中心基因，即ERBB2、GRB2、PTK2、PTPN11、ESR1和CCND1。我们还发现，西维来司他靶向脂多糖 (LPS) 处理后 4 小时（ICAM-1、PTGS2、RND1、BCL2A1、TNF、CA2 和 ADORA2A）、8 小时（ICAM-1、 PTGS2、RND1、BCL2A1、MMP1、BDKRB1 和 SLC40A1) 和 24 小时 (ICAM-1)。进一步的动物实验表明，西维来司他能够通过抑制 ICAM-1、VCAM-1 和 PTGS2 的过度表达并增加 PTK2 的磷酸化来减轻 LPS 诱导的 ALI。综上所述，生物信息学研究结果和实验数据表明，西维来司他对ALI/ARDS的治疗作用主要集中在ALI/ARDS的早期阶段，通过药理学调节炎症反应、血管内皮损伤和细胞凋亡相关分子。