Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis

Kossakowska, Anna E., Edwards, Dylan R. ORCID:, Lee, Samuel S., Urbanski, Lawrence S., Stabbler, Andrea L., Zhang, Chun-Li, Phillips, Blaine W., Zhang, Yikun and Urbanski, Stefan J. (1998) Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis. American Journal of Pathology, 153 (6). pp. 1895-902. ISSN 0002-9440

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A rat model of common bile duct ligation (BDL)-induced hepatic fibrosis was used to assess the expression and activities of collagen-degrading proteinases and their inhibitors during the progression of fibrosis. Expression of four members of the matrix metalloproteinase (MMP) family (MMP-2/gelatinase A, MMP-3, MMP-9/gelatinase B, and MMP-13) and three tissue inhibitors of metalloproteinases-1, -2, and -3 (TIMP-1, TIMP-2, and TIMP-3) were evaluated by Northern blot analysis of RNA from liver tissue isolated at 0, 2, 5, 10, 20, and 30 days after either a BDL or sham operation. In addition, we analyzed free gelatinase and TIMP activities by zymography and reverse zymography, respectively. We found that the proteolytic activities of MMP-2 and MMP-9 increased by 2 days after ligation, reached maximal levels at day 10, and remained high through the study period, whereas the gelatinolytic activities in plasma were unchanged. The increase in gelatinase activities was accompanied by an increase in the TIMP mRNA transcripts. TIMP-1 transcripts appeared at day 2, increased until day 10, and remained elevated throughout the study period. TIMP-2 and TIMP-3 transcripts become detectable on day 10 and remained stable afterwards. No corresponding increase in TIMP protein activity was detected by reverse zymography. This appears to result from the formation of TIMP/MMP complexes. These findings indicate a likely surplus in the BDL model of fibrosis of free gelatinases as compared with the TIMPs. Thus, excessive TIMP production is not a sufficient explanation for the observed extracellular matrix accumulation, but complex changes in the local MMP/TIMP balance may underlie the pathomechanisms of fibrosis.

Item Type: Article
Uncontrolled Keywords: animals,blotting, northern,blotting, western,collagenases,gelatinases,liver cirrhosis, experimental,male,matrix metalloproteinase 13,matrix metalloproteinase 2,matrix metalloproteinase 3,matrix metalloproteinase 9,metalloendopeptidases,rna, messenger,rats,rats, sprague-dawley,time factors,tissue inhibitor of metalloproteinase-1,tissue inhibitor of metalloproteinase-2,tissue inhibitor of metalloproteinase-3,tissue inhibitor of metalloproteinases
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Faculty of Science > Research Groups > Cells and Tissues
Depositing User: Pure Connector
Date Deposited: 25 Mar 2015 13:42
Last Modified: 19 Apr 2023 00:36
DOI: 10.1016/S0002-9440(10)65703-3

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