Reduced collagenolytic activity of matrix metalloproteinases and development of liver fibrosis in the aging rat

被引:48
作者
Gagliano, N
Arosio, B
Grizzi, F
Masson, S
Tagliabue, J
Dioguardi, N
Vergani, C
Annoni, G
机构
[1] Univ Milan, Dept Internal Med & Geriatr, I-20122 Milan, Italy
[2] IRCCS, Osped Maggiore, I-20122 Milan, Italy
[3] Univ Milano Bicocca, Milan, Italy
[4] Ist Clin Humanitias, Sci Direct, Milan, Italy
[5] Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy
关键词
liver; aging; fibrosis; matrix metalloproteinases;
D O I
10.1016/S0047-6374(01)00398-0
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Although moderate fibrosis is a histological hallmark of the aging liver. the molecular mechanisms underlying this phenomenon are little known. Here we provide a comprehensive description of hepatic collagen expression and metabolism during natural aging in rats, Interstitial collagen accumulated significantly in the oldest animals, mainly in the periportal area (P < 0.05, 19- vs, 2-month-old rats). This was ascribed to COL-III protein deposition (P < 0.05 vs. 2-month-old rats), rather than COL-I. Conversely the transcription activity of COL-III gene decreased (P < 0.05) during the considered lifespan (2-19-months). whereas COL-I and transforming growth fator-beta1 (TGF-beta1) mRNA content was substantially unchanged. In the aged rats, hepatic matrix metalloproteinases (NIMP) activity (both MMP-1 and MMP-2) dropped significantly (P < 0.05). with a concomitant increase of the inactive tissue inhibitor of MNIP (TIMP-1)/MMP-1 complex (P < 0.05). MMP-2 and TIMP-1 levels were bleakly affected. All together, these results suggest that during natural aging, (i) COL III is the protein that accumulates preferentially in the liver: (ii) liver fibrosclerosis is mainly explained by a reduced proteolytic activity of matrix MMP in which TIMP-1 seems to be a major regulating factor. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
引用
收藏
页码:413 / 425
页数:13
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