Participation of bile ductular cells in the pathological progression of non-alcoholic fatty liver disease
Participation of bile ductular cells in the pathological progression of non-alcoholic fatty liver disease
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DOI：
10.1136/jcp.2011.090175
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发表时间：
2011-07-01
影响因子：
3.4
通讯作者：
Nakanuma, Yasuni
中科院分区：
文献类型：
--
作者：
Chiba, Mayumi;Sasaki, Motoko;Nakanuma, Yasuni
目的非酒精性脂肪性肝病（NAFLD）代表了一系列病理状态，从简单的脂肪变性到肝纤维化，再发展到肝硬化。虽然已知活化的肝星状细胞（HSC）参与小叶内、窦周纤维化，但门脉和桥接纤维化的机制仍处于推测状态。本研究探讨了胆管在门静脉和间隔纤维化中的作用。结果CK 19阳性胆管随NAFLD分期和纤维化程度的加重而沿着增多，并与门脉炎症和纤维化程度相关。细胞衰老标志物; p16（INK 4a）和p21（WAF 1/Cip 1）阳性胆管细胞在第3和4阶段增加。这种衰老的胆管经常表达趋化蛋白，CCL 2（MCP-1），这可能是负责在门静脉和间隔纤维化和门静脉炎症的胆管周围的活化HSC的化学吸引。培养的小鼠肝星状细胞的迁移显着促进在培养的衰老小鼠胆管上皮细胞（BEC）的存在下，这种迁移是由CCL 2介导的衰老培养的BEC分泌。晚期肝实质中CK 7阳性的小梭形细胞可能分化为CK 19和CK 7阳性的门静脉周围胆管细胞。结论表达细胞衰老标志物和趋化因子的胆管增多可能参与了NAFLD进行性门静脉和桥接纤维化的发生。
Aims Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathological conditions, ranging from simple steatosis to hepatic fibrosis with progression to cirrhosis. While activated hepatic stellate cells (HSC) are known to be involved in intralobular, perisinuosidal fibrosis, the mechanisms of portal and bridging fibrosis remain speculative. This study investigated the roles of bile ductules in portal and septal fibrosis.Methods 48 liver biopsies were obtained from NAFLD patients. These cases were divided into four stages according to the Brunt classification.Results Bile ductules positive for CK19 were increased along with the progression of staging and fibrosis of NAFLD, and the increased bile ductules were associated with portal inflammation and fibrosis. The cellular senescence marker; p16(INK4a) and p21(WAF1/Cip1)-positive bile ductular cells were increased in stages 3 and 4. Such senescent bile ductules frequently express chemotactic protein, CCL2 (MCP-1), which may be responsible for chemoattraction of activated HSC around the bile ductules in portal and septal fibrosis and for portal inflammation. The migration of cultured mouse HSC was significantly facilitated in the presence of cultured senescent mouse biliary epithelial cells (BEC), and this migration was mediated by CCL2 secreted from senescent cultured BEC. Small spindle-like cells positive for CK7 alone in the hepatic parenchyma in the advanced stage seem to differentiate to periportal bile ductular cells positive for CK19 and CK7.Conclusions It seems possible that increased bile ductules expressing cellular senescence markers and chemokines are at least partly involved in the progressive portal and bridging fibrosis in NAFLD.