Disruption of tissue-type plasminogen activator gene in mice aggravated liver fibrosis

作者：Hsiao Yao; Zou Tie; Ling Chang Chun; Hu Hua; Tao Xian Mei; Song Hou Yan^*

来源：Journal of Gastroenterology and Hepatology, 2008, 23(7): E258-E264.

DOI：10.1111/j.1440-1746.2007.05100.x

• alpha-smooth muscle actin
• hepatic stellate cells
• matrix metalloproteinase
• tissue inhibitor of matrix metalloproteinase-1
• tissue-type plasminogen activator

Background and Aim: Tissue-type plasminogen activator (tPA) is one of the major components in the matrix proteolytic network whose role in the pathogenesis of liver fibrosis remains unknown. The aim of this study is to investigate the role of tPA in carbon tetrachloride (CCl4)-induced liver fibrosis.
Methods: Wild-type and tPA knockout mice (8 mice per group) were injected interperitoneumly with 25% CCl4 2 ml/kg twice per week as CCl4 administration groups and olive oil 2 ml/kg as controls. After 4 weeks, the livers of mice were removed under deep anesthesia and prepared for further studies such as histology, immunostaining, hydroxyproline assay, zymography and western blot analysis.
Results: Mice lacking tPA developed more severe morphological injury and displayed an increased deposition of collagen in the liver after CCl4 administration compared with wild-type counterparts. Deficiency of tPA increased alpha-smooth muscle actin expression in the mice livers. On the other hand, the decrease of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) activities, metalloproteinase-13 (MMP-13) expression and a marked increase of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) expression were found in the liver of CCl4 administrated tPA(-/-) mice compared with wild-type counterparts.
Conclusions: Deficiency of tPA aggravated liver fibrosis through promoting hepatic stellate cells (HSCs) activation and inhibiting ECM degradation by decreasing MMP-2, MMP-9 activities and disrupting the balance between MMP-13 and TIMP-1.

• 出版日期2008-7
• 单位复旦大学