Transcriptional profiling after bile duct ligation identifies PAI-1 as a contributor to cholestatic injury in mice
Transcriptional profiling after bile duct ligation identifies PAI-1 as a contributor to cholestatic injury in mice
复制标题
DOI：
10.1002/hep.20903
复制
发表时间：
2005-11-01
期刊：
影响因子：
13.5
通讯作者：
Heuckeroth, RO
中科院分区：
文献类型：
--
作者：
Wang, HT;Vohra, BPS;Heuckeroth, RO
肝外胆汁淤积导致复杂的损伤和修复过程，导致胆汁梗死形成、中性粒细胞浸润、胆管细胞和肝细胞增殖、细胞外基质重塑和纤维化。为了鉴定胆管梗阻后损伤和修复的早期分子机制，在胆管结扎（BDL）或假手术后24小时对肝组织进行微阵列分析。被鉴定的上调最多的基因编码纤溶酶原激活物抑制剂1（派-1，Serpine 1），其是阻断尿激酶纤溶酶原激活物（uPA）和组织型纤溶酶原激活物（tPA）活性的蛋白酶抑制剂。由于派-1、uPA和tPA影响生长因子和细胞因子加工以及细胞外基质重塑，我们通过比较野生型WT和派-1缺陷（派-1（-/-））小鼠BDL后的损伤和修复过程，评估派-1在胆汁淤积性肝损伤中的作用。派-1（-/-）小鼠在BDL后比WT动物有更少和更小的胆汁梗死，更少的中性粒细胞浸润，以及更高水平的胆管细胞和肝细胞增殖。此外，派-1（-/-）小鼠在BDL后比NW小鼠具有更高水平的tPA活化和成熟肝细胞生长因子（HGF），这表明派-1对HGF活化的作用严重影响胆汁淤积性肝损伤。BDL后派-1（-/-）小鼠中c-Met和Akt磷酸化水平升高进一步支持了这一点。总之，派-1缺乏可减轻小鼠BDL后的肝损伤。这些数据表明，抑制派-1可能会减轻胆汁淤积性肝病的肝损伤。
Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type WT and PAI-1-deficient (PAI-1(-/-)) mice after BDL. PAI-1(-/-) mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1(-/-) mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than NW mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1(-/-) mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases.