Department of Urologic Sciences, The Stone Centre at Vancouver General Hospital, Jack Bell Research Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada.
Department of Urology, Marien Hospital Herne, Ruhr-University of Bochum, Hölkeskampring 40, 44625, Herne, Germany.
Sci Rep. 2023 Apr 4;13(1):5492. doi: 10.1038/s41598-023-31885-1.
To explore the pathways and mechanisms driving inflammation and fibrosis in stented ureters. In total, six healthy female pigs underwent cystoscopic unilateral ureteral stent insertion (6 Fr). After 14 days indwelling time, ureteral tissue was harvested in three pigs, while the remaining three pigs had their stents removed, and were recovered for 7 days. Three separate pigs served as controls. Tissue from stented and contralateral ureters was analysed histologically to evaluate tissue remodelling and classify the degree of inflammation and fibrosis, while genome, proteome and immunohistochemistry analysis was performed to assess changes at the transcriptional and translational levels. Finally, immunofluorescence was used to characterize the cell composition of the immune response and pathways involved in inflammation and fibrosis. Statistical analysis was performed using GraphPad Prism and RStudio for Welch ANOVA, Kruskal-Wallis and Dunnett's T3 multiple comparison test. Stents cause significant inflammation and fibrosis of ureters. Gene set enrichment analysis confirmed fibrotic changes and tissue proliferation and suggests that epithelial-mesenchymal transition is a driver of fibrosis. Moreover, IL-6/JAK/STAT and TNFα via NF-κB signalling might contribute to chronic inflammation promoting a profibrotic environment. Immunostaining confirmed epithelial-mesenchymal transition in the urothelium and NF-κB expression in ureters stented for 14 days. Tissue alterations do not fully recover after 7 days. Histological evaluation showed that contralateral, unstented ureters are affected by mild inflammation. Our study showed that stenting has a significant impact on the ureter. Chronic inflammation and epithelial-mesenchymal transition are drivers of fibrosis, potentially impairing ureteral functionality in the long term. Furthermore, we observed mild inflammation in contralateral, unstented ureters.
探讨支架置入后输尿管炎症和纤维化的途径和机制。共 6 只健康雌性猪接受了经膀胱单侧输尿管支架置入术（6Fr）。留置 14 天后，3 只猪采集输尿管组织，而其余 3 只猪取出支架并恢复 7 天。另外 3 只猪作为对照。对支架置入侧和对侧输尿管组织进行组织学分析，以评估组织重塑，并对炎症和纤维化的程度进行分类，同时进行基因组、蛋白质组和免疫组织化学分析，以评估转录和翻译水平的变化。最后，通过免疫荧光对炎症和纤维化相关的免疫反应和途径中的细胞组成进行特征分析。GraphPad Prism 和 RStudio 用于 Welch ANOVA、Kruskal-Wallis 和 Dunnett's T3 多重比较检验进行统计分析。支架导致输尿管显著的炎症和纤维化。基因集富集分析证实了纤维化变化和组织增殖，并表明上皮-间充质转化是纤维化的驱动因素。此外，IL-6/JAK/STAT 和 TNFα 通过 NF-κB 信号通路可能导致慢性炎症，促进纤维形成环境。免疫染色证实了上皮-间充质转化在 14 天支架置入的尿路上皮中，并证实了 NF-κB 在输尿管中的表达。7 天后组织改变并未完全恢复。组织学评估显示，对侧未支架置入的输尿管受到轻度炎症的影响。我们的研究表明，支架对输尿管有显著影响。慢性炎症和上皮-间充质转化是纤维化的驱动因素，可能会长期损害输尿管功能。此外，我们观察到对侧未支架置入的输尿管有轻度炎症。
