Disruption of tissue-type plasminogen activator gene in mice aggravated liver fibrosis.
OBJECTIVE
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 (CCl(4))-induced liver fibrosis.


METHODS
Wild-type and tPA knockout mice (8 mice per group) were injected interperitoneumly with 25% CCl(4) 2 ml/kg twice per week as CCl(4) 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 CCl(4) 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 CCl(4) 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.
Hsiao
Yao
Y
Department of Molecular Genetics, Key Laboratory of Molecular Medicine, Ministry of Education, Shanghai Medical School, Fudan University, Shanghai, China.
Zou
Tie
T
Ling
Chang-Chun
CC
Hu
Hua
H
Tao
Xian-Mei
XM
Song
Hou-Yan
HY
D000199:Actins / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012720:Severity of Illness Index; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen; D002251:Carbon Tetrachloride; D010959:Tissue Plasminogen Activator; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse