Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA.
The Digestive Health Institute, Aurora, Colorado, USA.
Hepatol Commun. 2024 Nov 25;8(12). doi: 10.1097/HC9.0000000000000589. eCollection 2024 Dec 1.
Intestinal inflammation is a common factor in ~70% of patients diagnosed with primary sclerosing cholangitis. The TNF∆ARE+/- mouse overexpresses TNFα and spontaneously develops ileitis after weaning. The aim of this study was to examine the influence of ileitis and TNFα overexpression on hepatic injury, fibrosis, inflammation, and bile acid homeostasis.
Using serum, hepatic, and ileal tissue isolated from 24- to 26-week-old C57BL/6 and TNF∆ARE+/- mice, hepatic injury and fibrosis, inflammation, ductal proliferation, and regulation of bile acid synthesis were assessed by immunohistochemical and quantitative PCR methods.
Compared to age-matched C57BL/6 mice, TNF∆ARE+/- mice exhibited increased serum AST, ALT, and serum bile acids, which corresponded to increased hepatic picrosirius red staining, and an increase in hepatic mRNA expression of Tgfb, Timp1, Col1a1, and MMP9 supporting induction of fibrosis. Examining inflammation, immunohistochemical staining revealed a significant periportal increase in MPO+ neutrophils, CD3+ lymphocytes, and a panlobular increase in F4/80+ macrophages. Importantly, periportal inflammation corresponded to significantly increased proinflammatory chemokines as well as hepatic cytokeratin 7 staining supporting increased ductular proliferation. In the liver, increased mRNA expression of bile acid transporters was associated with suppression of classical but not alternative bile acid synthesis. In the ileum, increased inflammation correlated with suppression of Nr1h4 and increased Fgf15 and Nr0b2 mRNA expression.
Increased TNFα expression is sufficient to promote both intestinal and hepatobiliary inflammation and fibrotic injury and contributes to hepatic dysregulation of FXR signaling and bile acid homeostasis. Overall, these results suggest that the TNF∆ARE+/- mouse may be a useful model for studying chronic hepatic inflammation.
肠道炎症是约 70%原发性硬化性胆管炎患者的共同因素。TNF∆ARE+/- 小鼠过度表达 TNFα，断奶后会自发发展为回肠炎。本研究旨在研究回肠炎和 TNFα过表达对肝损伤、纤维化、炎症和胆汁酸稳态的影响。
使用来自 24-26 周龄 C57BL/6 和 TNF∆ARE+/- 小鼠的血清、肝和回肠组织，通过免疫组织化学和定量 PCR 方法评估肝损伤和纤维化、炎症、胆管增殖和胆汁酸合成的调节。
与同龄 C57BL/6 小鼠相比，TNF∆ARE+/- 小鼠的血清 AST、ALT 和血清胆汁酸升高，相应的肝组织天狼星红染色增加，肝组织 Tgfb、Timp1、Col1a1 和 MMP9 的 mRNA 表达增加，支持纤维化的诱导。检查炎症时，免疫组织化学染色显示门静脉周围的 MPO+中性粒细胞、CD3+淋巴细胞和全小叶的 F4/80+巨噬细胞显著增加。重要的是，门静脉周围的炎症与显著增加的促炎趋化因子以及支持胆管增殖的肝细胞角蛋白 7 染色相对应。在肝脏中，胆汁酸转运体的 mRNA 表达增加与经典但非替代胆汁酸合成的抑制有关。在回肠中，炎症的增加与 Nr1h4 的抑制以及 Fgf15 和 Nr0b2 mRNA 表达的增加相关。
TNFα表达的增加足以促进肠道和肝胆炎症及纤维化损伤，并导致 FXR 信号和胆汁酸稳态的肝脏失调。总的来说，这些结果表明 TNF∆ARE+/- 小鼠可能是研究慢性肝炎症的有用模型。
