Gonçalves Josiane O, Mafra Cleiton A M, Castro Isac de, Cogliati Bruno, Teodoro Walcy R, Bando Silvia Y, Serafini Suellen, Moreira-Filho Carlos A, Tannuri Uenis, Tannuri Ana C A
Division of Pediatric Surgery, Pediatric Liver Transplant Unit, and Pediatric Surgery Research Laboratory (LIM 30), University of São Paulo School of Medicine, São Paulo, SP, Brazil.
Department of Pediatrics, University of São Paulo School of Medicine, São Paulo, SP, Brazil.
Pediatr Res. 2025 Jul 24. doi: 10.1038/s41390-025-04272-x.
The selective bile duct ligation (sBDL) model has been proposed to study fibrosis progression in segmental cholestasis, replicating histopathological features of biliary obstruction in both liver parenchyma with biliary obstruction (BO) and without biliary obstruction (WBO). However, the molecular mechanisms driving fibrogenesis in WBO parenchyma remain unclear. This study aimed to characterize gene expression and histological alterations in fibrogenesis using the sBDL model.
Liver samples were collected at 1, 4, and 8 weeks post-surgery from both BO and WBO parenchyma, undergoing histological, immunohistochemical, biochemical, and molecular analyses.
Differentially expressed genes (DEGs) were associated to inflammatory response, extracellular matrix production, angiogenesis, and negative regulation of peptidase activity. Histologically, ductular proliferation, inflammatory infiltration, and collagen deposition were observed in both BO and WBO parenchyma, with more pronounced inflammation and hepatocellular degeneration in BO. BO parenchyma showed more pathways related to disease progression. In contrast, pathways related to cellular senescence and the PI3K-Akt signaling, suggesting suppression of apoptosis and cell proliferation.
The sBDL model mirrors key aspects of human biliary fibrosis, offering novel molecular insights into fibrogenesis in segmental cholestasis and serving as a valuable tool for developing diagnostic and therapeutic strategies.
This study demonstrates that hepatic fibrogenesis extends beyond regions directly affected by biliary obstruction, involving non-obstructed liver parenchyma. Using the selective bile duct ligation (sBDL) model, we identified key molecular pathways associated with fibrogenesis in segmental cholestasis. Our findings provides new insights into the mechanisms of cholestatic fibrosis and highlighting the sBDL model as a valuable preclinical tool. These results may inform the development of novel therapeutic strategies for treating biliary fibrosis.
选择性胆管结扎（sBDL）模型已被用于研究节段性胆汁淤积中的纤维化进展，该模型可复制肝实质中存在胆管梗阻（BO）和不存在胆管梗阻（WBO）时胆汁淤积的组织病理学特征。然而，驱动WBO实质纤维化的分子机制仍不清楚。本研究旨在利用sBDL模型描述纤维化过程中的基因表达和组织学改变。
在术后1、4和8周从BO和WBO实质中收集肝脏样本，进行组织学、免疫组化、生化和分子分析。
差异表达基因（DEG）与炎症反应、细胞外基质产生、血管生成和肽酶活性的负调控相关。组织学上，在BO和WBO实质中均观察到小胆管增生、炎症浸润和胶原沉积，其中BO中的炎症和肝细胞变性更为明显。BO实质显示出更多与疾病进展相关的通路。相比之下，WBO实质中的通路与细胞衰老和PI3K-Akt信号传导相关，提示细胞凋亡和增殖受到抑制。
sBDL模型反映了人类胆汁纤维化的关键方面，为节段性胆汁淤积中的纤维化形成提供了新的分子见解，并成为开发诊断和治疗策略的有价值工具。
本研究表明，肝纤维化不仅局限于受胆管梗阻直接影响的区域，还涉及未梗阻的肝实质。通过使用选择性胆管结扎（sBDL）模型，我们确定了节段性胆汁淤积中与纤维化形成相关的关键分子通路。我们的发现为胆汁淤积性纤维化的机制提供了新的见解，并突出了sBDL模型作为一种有价值的临床前工具。这些结果可能为治疗胆汁纤维化新治疗策略的开发提供参考。
