Zhang Mengran, Lu Hongping, Cheng Jun
Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
Hebei Utu Pharmaceutical Company Ltd., Shijiazhuang, Hebei Province, China.
Braz J Med Biol Res. 2025 Aug 22;58:e14540. doi: 10.1590/1414-431X2025e14540. eCollection 2025.
Statins have been shown to have antifibrotic effects on various tissues and organs, but their ability to improve chronic colitis-associated intestinal fibrosis and their mechanisms of action remain unclear. The objective of this study was to investigate the role of pitavastatin in chronic colitis-associated intestinal fibrosis and its possible mechanisms. We established a mouse model of chronic colitis-associated intestinal fibrosis through repeated administration of dextran sodium sulfate (DSS) and treated the mice with pitavastatin. The severity of intestinal fibrosis, serum inflammatory factor levels, and expression levels of intestinal fibrosis-related genes in mice were assessed using pathological histological staining, immunohistochemical staining, reverse-transcription PCR, RNA sequencing, and enzyme-linked immunosorbent assay. In vitro, we treated a human colon fibroblast cell line (CCD-18Co) with or without transforming growth factor-β1 stimulation using pitavastatin. Western blot, Cell Counting Kit-8 assay, and Transwell assay were used to analyze the activation of colonic fibroblasts, protein expression levels of genes related to intestinal fibrosis, and cell proliferation and migration abilities. Pitavastatin significantly attenuated DSS-induced chronic colitis and intestinal fibrosis. In vitro, pitavastatin concentration-dependently inhibited the activation of CCD-18Co cells, significantly reduced the expression levels of the intestinal fibrosis-related proteins Col1A1, IGF-1, IGF-1R, MMP-3, and TIMP-1, and significantly inhibited cell proliferation and migration while markedly increasing MMP-9 protein expression. Additionally, after silencing the IGF-1 and IGF-1R genes in CCD-18Co cells, the promotion of MMP-9 expression by pitavastatin was significantly inhibited. These findings suggest that pitavastatin may be a promising antifibrotic drug for future treatment of intestinal fibrosis.
他汀类药物已被证明对各种组织和器官具有抗纤维化作用，但其改善慢性结肠炎相关肠道纤维化的能力及其作用机制仍不清楚。本研究的目的是探讨匹伐他汀在慢性结肠炎相关肠道纤维化中的作用及其可能机制。我们通过反复给予葡聚糖硫酸钠（DSS）建立了慢性结肠炎相关肠道纤维化小鼠模型，并用匹伐他汀治疗小鼠。使用病理组织学染色、免疫组织化学染色、逆转录PCR、RNA测序和酶联免疫吸附测定法评估小鼠肠道纤维化的严重程度、血清炎症因子水平和肠道纤维化相关基因的表达水平。在体外，我们用匹伐他汀处理人结肠成纤维细胞系（CCD-18Co），并给予或不给予转化生长因子-β1刺激。采用蛋白质免疫印迹法、细胞计数试剂盒-8法和Transwell法分析结肠成纤维细胞的活化、肠道纤维化相关基因的蛋白表达水平以及细胞增殖和迁移能力。匹伐他汀显著减轻了DSS诱导的慢性结肠炎和肠道纤维化。在体外，匹伐他汀浓度依赖性地抑制CCD-18Co细胞的活化，显著降低肠道纤维化相关蛋白Col1A1、IGF-1、IGF-1R、MMP-3和TIMP-1的表达水平，并显著抑制细胞增殖和迁移，同时显著增加MMP-9蛋白表达。此外，在使CCD-18Co细胞中的IGF-1和IGF-1R基因沉默后，匹伐他汀对MMP-9表达的促进作用被显著抑制。这些发现表明，匹伐他汀可能是未来治疗肠道纤维化的一种有前景的抗纤维化药物。
