The role of hepatic stellate cells and transforming growth factor-β1 in cystic fibrosis liver disease
The role of hepatic stellate cells and transforming growth factor-β1 in cystic fibrosis liver disease
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DOI：
10.1016/s0002-9440(10)61117-0
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发表时间：
2002-05-01
影响因子：
6
通讯作者：
Ramm, GA
中科院分区：
文献类型：
--
作者：
Lewindon, PJ;Pereira, TN;Ramm, GA
肝脏疾病导致囊性纤维化患者多小叶肝硬化的显著发病率和死亡率。胆汁转运异常和胆道纤维化在囊性纤维化相关性肝病（CFLD）的发病机制中涉及胆道生理异常，但将胆道事件与纤维化联系起来的介质尚不清楚。活化的肝星状细胞（hsc）是一系列肝脏疾病中纤维化的卓越介质。造血干细胞生成基质的主要刺激因子是细胞因子转化生长因子(TGF)- β(1)。在CFLD中，hsc的作用和tgf - β(1)的来源尚未得到评估。对38例CFLD患儿的肝活检组织进行分析。通过前胶原α (1)(I) mRNA和a-平滑肌肌动蛋白的共定位鉴定，活化的hsc被证明是胆管周围纤维化和瘢痕组织前缘过量胶原生成的细胞来源。tgf - β蛋白和tgf - β (1) mRNA的表达主要由胆管上皮细胞表达。tgf - β(1)表达与肝纤维化和与CFLD相关的门静脉束组织学异常百分比显著相关。本研究证实了HSC在与CFLD相关的纤维形成中的明确作用，并建立了通过胆管上皮细胞产生tgf - β(1)诱导HSC胶原基因表达的潜在机制。
Liver disease causes significant morbidity and mortality from multilobular cirrhosis in patients with cystic fibrosis. Abnormal bile transport and biliary fibrosis implicate abnormal biliary physiology in the pathogenesis of cystic fibrosis-associated liver disease (CFLD), yet the mediators linking biliary events to fibrosis remain unknown. Activated hepatic stellate cells (HSCs) are the pre-eminent mediators of fibrosis in a range of hepatic disorders. The dominant stimulus for matrix production by HSCs is the cytokine transforming growth factor (TGF)-beta(1). In CFLD, the role of HSCs and the source of TGF-beta(1) have not been evaluated. Liver biopsy tissue obtained from 38 children with CFLD was analyzed. Activated HSCs, identified by co-localization of procollagen alpha(1)(I) mRNA and a-smooth muscle actin, were demonstrated as the cellular source of excess collagen production in the fibrosis surrounding the bile ducts and the advancing edge of scar tissue. TGF-beta protein and TGF-beta(1) mRNA expression were shown to be predominantly expressed by bile duct epithelial cells. TGF-beta(1) expression was significantly correlated with both hepatic fibrosis and the percentage of portal tracts showing histological abnormalities associated with CFLD. This study demonstrates a definitive role for HSCs in fibrogenesis associated with CFLD and establishes a potential mechanism for the induction of HSC collagen gene expression through the production of TGF-beta(1) by bile duct epithelial cells.