Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China.
Department of Emergency, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
Front Immunol. 2022 May 11;13:882774. doi: 10.3389/fimmu.2022.882774. eCollection 2022.
Sepsis is a leading cause of morbidity and mortality in the intensive care unit, which is caused by unregulated inflammatory response leading to organ injuries. Ulinastatin (UTI), an immunomodulatory agent, is widely used in clinical practice and is associated with improved outcomes in sepsis. But its underlying mechanisms are largely unknown. Our study integrated bulk and single cell RNA-seq data to systematically explore the potential mechanisms of the effects of UTI in sepsis. After adjusting for potential confounders in the negative binomial regression model, there were more genes being downregulated than being upregulated in the UTI group. These down-regulated genes were enriched in the neutrophil involved immunity such as neutrophil activation and degranulation, indicating the immunomodulatory effects of UTI is mediated regulation of neutrophil activity. By deconvoluting the bulk RNA-seq samples to obtain fractions of cell types, the Myeloid-derived suppressor cells (MDSC) were significantly expanded in the UTI treated samples. Further cell-cell communication analysis revealed some signaling pathways such as ANEEXIN, GRN and RESISTIN that might be involved in the immunomodulatory effects of UTI. The study provides a comprehensive reference map of transcriptional states of sepsis treated with UTI, as well as a general framework for studying UTI-related mechanisms.
脓毒症是重症监护病房发病率和死亡率的主要原因，是由不受调节的炎症反应导致器官损伤引起的。乌司他丁（UTI）是一种免疫调节剂，广泛应用于临床实践，并与脓毒症的改善结局相关。但其潜在机制在很大程度上尚不清楚。我们的研究整合了批量和单细胞 RNA-seq 数据，系统地探讨了 UTI 在脓毒症中的作用的潜在机制。在负二项回归模型中调整潜在混杂因素后，UTI 组下调的基因多于上调的基因。这些下调的基因富集于中性粒细胞参与的免疫，如中性粒细胞的激活和脱颗粒，表明 UTI 的免疫调节作用是通过调节中性粒细胞的活性来介导的。通过对批量 RNA-seq 样本进行去卷积以获得细胞类型的分数，在 UTI 处理的样本中髓源性抑制细胞（MDSC）显著扩增。进一步的细胞间通讯分析显示，一些信号通路，如 ANEEXIN、GRN 和 RESISTIN，可能参与了 UTI 的免疫调节作用。该研究为 UTI 治疗脓毒症的转录状态提供了全面的参考图谱，并为研究 UTI 相关机制提供了一个通用框架。
