PDF(Pubmed)
Abstract：
UNASSIGNED: Capillary leak syndrome (CLS) is an intermediary phase between severe acute pancreatitis (SAP) and multiple organ failure. As a result, CLS is of clinical importance for enhancing the prognosis of SAP. Plakophilin2 (PKP2), an essential constituent of desmosomes, plays a critical role in promoting connections between epithelial cells. However, the function and mechanism of PKP2 in CLS in SAP are not clear at present.
UNASSIGNED: We detected the expression of PKP2 in mice pancreatic tissue by transcriptome sequencing and bioinformatics analysis. PKP2 was overexpressed and knocked down to assess its influence on cell permeability, the cytoskeleton, tight junction molecules, cell adhesion junction molecules, and associated pathways.
UNASSIGNED: PKP2 expression was increased in the pancreatic tissues of SAP mice and human umbilical vein endothelial cells (HUVECs) after lipopolysaccharide (LPS) stimulation. PKP2 overexpression not only reduced endothelial cell permeability but also improved cytoskeleton relaxation in response to acute inflammatory stimulation. PKP2 overexpression increased levels of ZO-1, occludin, claudin1, β-catenin, and connexin43. The overexpression of PKP2 in LPS-induced HUVECs counteracted the inhibitory effect of SB203580 (a p38/MAPK signaling pathway inhibitor) on the p38/MAPK signaling pathway, thereby restoring the levels of ZO-1, β-catenin, and claudin1. Additionally, PKP2 suppression eliminated the enhanced levels of ZO-1, β-catenin, occludin, and claudin1 induced by dehydrocorydaline. We predicted that the upstream transcription factor PPARγregulates PKP2 expression, and our findings demonstrate that the PPARγactivator rosiglitazone significantly upregulates PKP2, whereas its antagonist GW9662 down-regulates PKP2. Administration of rosiglitazone significantly reduced the increase in HUVECs permeability stimulated by LPS. Conversely, PKP2 overexpression counteracted the GW9662-induced reduction in ZO-1, phosphorylated p38/p38, and claudin1.
UNASSIGNED: The activation of the p38/MAPK signaling pathway by PKP2 mitigates CLS in SAP. PPARγactivator rosiglitazone can up-regulate PKP2. Overall, directing efforts toward PKP2 could prove to be a feasible treatment approach for effectively managing CLS in SAP.
UNASSIGNED: We detected the expression of PKP2 in mice pancreatic tissue by transcriptome sequencing and bioinformatics analysis. PKP2 was overexpressed and knocked down to assess its influence on cell permeability, the cytoskeleton, tight junction molecules, cell adhesion junction molecules, and associated pathways.
UNASSIGNED: PKP2 expression was increased in the pancreatic tissues of SAP mice and human umbilical vein endothelial cells (HUVECs) after lipopolysaccharide (LPS) stimulation. PKP2 overexpression not only reduced endothelial cell permeability but also improved cytoskeleton relaxation in response to acute inflammatory stimulation. PKP2 overexpression increased levels of ZO-1, occludin, claudin1, β-catenin, and connexin43. The overexpression of PKP2 in LPS-induced HUVECs counteracted the inhibitory effect of SB203580 (a p38/MAPK signaling pathway inhibitor) on the p38/MAPK signaling pathway, thereby restoring the levels of ZO-1, β-catenin, and claudin1. Additionally, PKP2 suppression eliminated the enhanced levels of ZO-1, β-catenin, occludin, and claudin1 induced by dehydrocorydaline. We predicted that the upstream transcription factor PPARγregulates PKP2 expression, and our findings demonstrate that the PPARγactivator rosiglitazone significantly upregulates PKP2, whereas its antagonist GW9662 down-regulates PKP2. Administration of rosiglitazone significantly reduced the increase in HUVECs permeability stimulated by LPS. Conversely, PKP2 overexpression counteracted the GW9662-induced reduction in ZO-1, phosphorylated p38/p38, and claudin1.
UNASSIGNED: The activation of the p38/MAPK signaling pathway by PKP2 mitigates CLS in SAP. PPARγactivator rosiglitazone can up-regulate PKP2. Overall, directing efforts toward PKP2 could prove to be a feasible treatment approach for effectively managing CLS in SAP.
摘要：
■毛细血管渗漏综合征（CLS）是重症急性胰腺炎（SAP）和多器官衰竭之间的中间阶段。因此,CLS对提高SAP的预后具有重要的临床意义。Plakophilin2(PKP2),桥粒的重要组成部分，在促进上皮细胞之间的连接中起着至关重要的作用。然而,PKP2在SAPCLS中的作用及作用机制目前尚不明确。
■我们通过转录组测序和生物信息学分析检测了PKP2在小鼠胰腺组织中的表达。PKP2过表达并敲低以评估其对细胞通透性的影响，细胞骨架，紧密连接分子，细胞粘附连接分子，和相关的途径。
■脂多糖（LPS）刺激后，SAP小鼠和人脐静脉内皮细胞（HUVEC）的胰腺组织中PKP2的表达增加。PKP2过表达不仅降低了内皮细胞的通透性，而且改善了对急性炎症刺激的细胞骨架松弛。PKP2过表达增加了ZO-1，闭塞蛋白，claudin1，β-catenin，和Connexin43.PKP2在LPS诱导的HUVECs中的过表达抵消了SB203580(p38/MAPK信号通路抑制剂)对p38/MAPK信号通路的抑制作用,从而恢复ZO-1，β-连环蛋白的水平，还有Claudin1.此外,PKP2抑制消除了ZO-1，β-catenin，occludin,和脱氢紫藤碱诱导的claudin1。我们预测上游转录因子PPARγ调控PKP2的表达,我们的研究结果表明，PPARγ激活剂罗格列酮显著上调PKP2，而其拮抗剂GW9662下调PKP2。罗格列酮的施用显著降低了LPS刺激的HUVECs通透性的增加。相反，PKP2过表达抵消了GW9662诱导的ZO-1，磷酸化p38/p38和claudin1的减少。
■PKP2对p38/MAPK信号通路的激活减轻了SAP中的CLS。PPARγ激活剂罗格列酮可以上调PKP2。总的来说,针对PKP2的努力可能被证明是有效管理SAPCLS的可行治疗方法。
■我们通过转录组测序和生物信息学分析检测了PKP2在小鼠胰腺组织中的表达。PKP2过表达并敲低以评估其对细胞通透性的影响，细胞骨架，紧密连接分子，细胞粘附连接分子，和相关的途径。
■脂多糖（LPS）刺激后，SAP小鼠和人脐静脉内皮细胞（HUVEC）的胰腺组织中PKP2的表达增加。PKP2过表达不仅降低了内皮细胞的通透性，而且改善了对急性炎症刺激的细胞骨架松弛。PKP2过表达增加了ZO-1，闭塞蛋白，claudin1，β-catenin，和Connexin43.PKP2在LPS诱导的HUVECs中的过表达抵消了SB203580(p38/MAPK信号通路抑制剂)对p38/MAPK信号通路的抑制作用,从而恢复ZO-1，β-连环蛋白的水平，还有Claudin1.此外,PKP2抑制消除了ZO-1，β-catenin，occludin,和脱氢紫藤碱诱导的claudin1。我们预测上游转录因子PPARγ调控PKP2的表达,我们的研究结果表明，PPARγ激活剂罗格列酮显著上调PKP2，而其拮抗剂GW9662下调PKP2。罗格列酮的施用显著降低了LPS刺激的HUVECs通透性的增加。相反，PKP2过表达抵消了GW9662诱导的ZO-1，磷酸化p38/p38和claudin1的减少。
■PKP2对p38/MAPK信号通路的激活减轻了SAP中的CLS。PPARγ激活剂罗格列酮可以上调PKP2。总的来说,针对PKP2的努力可能被证明是有效管理SAPCLS的可行治疗方法。
