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重症急性胰腺炎大鼠肺微血管内皮细胞微管稳定性的调节：清胰汤是一种潜在的CDK5抑制剂。

Regulation of Microtubule Stability in Pulmonary Microvascular Endothelial Cells in Rats with Severe Acute Pancreatitis: Qingyi Decoction is a Potential CDK5 Inhibitor.

作者信息

Cao Yinan, Li Fan, Sun Zhenxuan, Liu Jin, Liu Jie, Yang Qi, Ge Peng, Luo Yalan, Chen Hailong

机构信息

Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People's Republic of China.

Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China.

出版信息

J Inflamm Res. 2024 Apr 24;17:2513-2530. doi: 10.2147/JIR.S451755. eCollection 2024.

DOI:10.2147/JIR.S451755
PMID:38699595
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11063490/
Abstract

PURPOSE

Explore the therapeutic effects and regulatory mechanism of Qingyi Decoction (QYD) on severe acute pancreatitis (SAP) associated acute lung injury (ALI).

METHODS

We identified the constituents absorbed into the blood of QYD based on a network pharmacological strategy. The differentially expressed genes from the GEO database were screened to identify the critical targets of QYD treatment of SAP-ALI. The SAP-ALI rat model was constructed.Some methods were used to evaluate the efficacy and mechanism of QYD in treating SAP-ALI. LPS-stimulated pulmonary microvascular endothelial cell injury simulated the SAP-induced pulmonary endothelial injury model. We further observed the therapeutic effect of QYD and CDK5 plasmid transfection on endothelial cell injury.

RESULTS

18 constituents were absorbed into the blood, and 764 targets were identified from QYD, 25 of which were considered core targets for treating SAP-ALI. CDK5 was identified as the most critical gene. The results of differential expression analysis showed that the mRNA expression level of CDK5 in the blood of SAP patients was significantly up-regulated compared with that of healthy people. Animal experiments have demonstrated that QYD can alleviate pancreatic and lung injury inflammatory response and reduce the upregulation of CDK5 in lung tissue. QYD or CDK5 inhibitors could decrease the expression of NFAT5 and GEF-H1, and increase the expression of ACE-tub in SAP rat lung tissue. Cell experiments proved that QYD could inhibit the expression of TNF-α and IL-6 induced by LPS. Immunofluorescence results suggested that QYD could alleviate the cytoskeleton damage of endothelial cells, and the mechanism might be related to the inhibition of CDK5-mediated activation of NFAT5, GEF-H1, and ACE-tub.

CONCLUSION

CDK5 has been identified as a critical target for pulmonary endothelial injury of SAP-ALI. QYD may partially alleviate microtubule disassembly by targeting the CDK5/NFAT5/GEF-H1 signaling pathway, thus relieving SAP-induced pulmonary microvascular endothelial cell injury.

摘要

目的

探讨清胰汤（QYD）对重症急性胰腺炎（SAP）相关性急性肺损伤（ALI）的治疗作用及调控机制。

方法

基于网络药理学策略鉴定QYD吸收入血的成分。从GEO数据库筛选差异表达基因，以确定QYD治疗SAP-ALI的关键靶点。构建SAP-ALI大鼠模型，采用多种方法评估QYD治疗SAP-ALI的疗效及机制。利用脂多糖刺激的肺微血管内皮细胞损伤模拟SAP诱导的肺内皮损伤模型，进一步观察QYD及CDK5质粒转染对内皮细胞损伤的治疗作用。

结果

鉴定出18种吸收入血的成分，从QYD中确定了764个靶点，其中25个被认为是治疗SAP-ALI的核心靶点。CDK5被鉴定为最关键的基因。差异表达分析结果显示，与健康人相比，SAP患者血液中CDK5的mRNA表达水平显著上调。动物实验表明，QYD可减轻胰腺和肺损伤的炎症反应，并降低肺组织中CDK5的上调。QYD或CDK5抑制剂可降低SAP大鼠肺组织中NFAT5和GEF-H1的表达，并增加ACE-tub的表达。细胞实验证明，QYD可抑制脂多糖诱导的TNF-α和IL-6的表达。免疫荧光结果提示，QYD可减轻内皮细胞的细胞骨架损伤，其机制可能与抑制CDK5介导的NFAT5、GEF-H1和ACE-tub的激活有关。

结论

CDK5已被确定为SAP-ALI肺内皮损伤的关键靶点。QYD可能通过靶向CDK5/NFAT5/GEF-H1信号通路部分减轻微管解聚，从而减轻SAP诱导的肺微血管内皮细胞损伤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7869/11063490/9e6f91e452ef/JIR-17-2513-g0010.jpg
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