The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China.
The Clinical Medical College, Ningxia Medical University, Yinchuan 750004, China.
Int J Mol Sci. 2021 Nov 30;22(23):13008. doi: 10.3390/ijms222313008.
Peritonitis caused by LPS is a severe clinical challenge, which causes organ damage and death. However, the mechanism of LPS-induced peritonitis has not been fully revealed yet. Here, we investigated the transcriptome profile of the peritoneal tissue of LPS-induced peritonitis in mice. A model of LPS-induced peritonitis in mice was established (LPS 10 mg/kg, i.p.), and the influence of TAK 242 (TLR4 inhibitor) on the level of inflammatory cytokines in mouse peritoneal lavage fluid was investigated by using an ELISA test. Next, the peritoneal tissues of the three groups of mice (Control, LPS, and LPS+TAK 242) ( = 6) were isolated and subjected to RNA-seq, followed by a series of bioinformatics analyses, including differentially expressed genes (DEGs), enrichment pathway, protein-protein interaction, and transcription factor pathway. Then, qPCR verified-hub genes that may interact with TAK 242 were obtained. Subsequently, the three-dimensional structure of hub proteins was obtained by using homology modeling and molecular dynamics optimization (300 ns). Finally, the virtual docking between TAK 242 and hub proteins was analyzed. Our results showed that TAK 242 significantly inhibited the production of inflammatory cytokines in the peritoneal lavage fluid of mice with peritonitis, including IL-6, IFN-γ, IL-1β, NO, and TNF-α. Compared with the Control group, LPS treatment induced 4201 DEGs (2442 down-regulated DEGs and 1759 up-regulated DEGs). Compared with the LPS group, 30 DEGs were affected by TAK 242 (8 down-regulated DEGs and 22 up-regulated DEGs). A total of 10 TAK 242-triggered hub genes were obtained, and the possible docking modes between TAK 242 and hub proteins were acquired. Overall, our data demonstrated that a large number of DEGs were affected in LPS-triggered peritonitis mice. Moreover, the TLR4 inhibitor TAK 242 is capable of suppressing the inflammatory response of LPS-induced peritonitis. Our work provides clues for understanding the pathogenesis of LPS-induced peritonitis in mice.
脂多糖（LPS）引起的腹膜炎是一种严重的临床挑战，它会导致器官损伤和死亡。然而，LPS 诱导腹膜炎的机制尚未完全揭示。在这里，我们研究了 LPS 诱导的腹膜炎小鼠腹膜组织的转录组谱。建立了 LPS 诱导的腹膜炎小鼠模型（LPS10mg/kg，腹腔注射），通过 ELISA 试验研究了 TLR4 抑制剂 TAK242 对小鼠腹腔灌洗液中炎症细胞因子水平的影响。接下来，分离三组小鼠（对照、LPS 和 LPS+TAK242）（n=6）的腹膜组织，进行 RNA-seq，然后进行一系列生物信息学分析，包括差异表达基因（DEGs）、富集通路、蛋白质-蛋白质相互作用和转录因子通路。然后，通过 qPCR 验证了可能与 TAK242 相互作用的 hub 基因。随后，通过同源建模和分子动力学优化（300ns）获得了 hub 蛋白的三维结构。最后，分析了 TAK242 与 hub 蛋白之间的虚拟对接。我们的结果表明，TAK242 显著抑制了腹膜炎小鼠腹腔灌洗液中炎症细胞因子的产生，包括白细胞介素-6（IL-6）、干扰素-γ（IFN-γ）、白细胞介素-1β（IL-1β）、一氧化氮（NO）和肿瘤坏死因子-α（TNF-α）。与对照组相比，LPS 处理诱导了 4201 个 DEGs（2442 个下调 DEGs 和 1759 个上调 DEGs）。与 LPS 组相比，TAK242 影响了 30 个 DEGs（8 个下调 DEGs 和 22 个上调 DEGs）。获得了 10 个 TAK242 触发的 hub 基因，获得了 TAK242 和 hub 蛋白之间可能的对接模式。总的来说，我们的数据表明，大量的 DEGs 在 LPS 诱导的腹膜炎小鼠中受到影响。此外，TLR4 抑制剂 TAK242 能够抑制 LPS 诱导的腹膜炎的炎症反应。我们的工作为理解 LPS 诱导的腹膜炎小鼠的发病机制提供了线索。
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