Mutation in collagen-I that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration

被引:150
作者
Issa, R
Zhou, XY
Trim, N
Millward-Sadler, H
Krane, S
Benyon, C
Iredale, J
机构
[1] Univ Southampton, Southampton Gen Hosp, Liver Res Grp, Southampton SO19 6YD, Hants, England
[2] Univ Southampton, Southampton Gen Hosp, Dept Histopathol Infect Inflammat & Repair, Southampton SO19 6YD, Hants, England
[3] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA
基金
英国医学研究理事会;
关键词
apoptosis; metalloproteinase (MMP); tissue inhibitor of metalloproteinase (TIMP); hepatic regeneration;
D O I
10.1096/fj.02-0494fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 [生物化学与分子生物学]; 081704 [应用化学];
摘要
Collagen-I, which predominates in the neomatrix of fibrotic liver, regulates hepatocyte and hepatic stellate cell (HSC) phenotypes. Recovery from liver fibrosis is accompanied by hepatocyte regeneration, matrix degradation, and HSC apoptosis. Using mice bearing a mutated collagen-I gene (r/r mice), which confers resistance to collagenase degradation, we have investigated the hypothesis that collagen-I degradation is critical to HSC apoptosis and hepatocyte regeneration during recovery from liver fibrosis. During a 28-day recovery period after 8 wk of CCl4 treatment, wild-type (WT) livers had significantly (43%) decreased hydroxyproline (OHP) content. In r/r livers, however, OHP content remained elevated at peak fibrosis levels. Expressed markers of activated HSC (alpha-smooth muscle actin, collagen-I), elevated at peak fibrosis, dropped to control levels in WT livers after 28 days but remained raised in the r/r livers. Moreover, relative to WT livers, r/r livers had significantly reduced stellate cell apoptosis and hepatocyte regeneration during the recovery period. Using extracted collagen-I from each genotype as culture substrata, relative to r/r, we show that WT collagen-I promotes hepatocyte proliferation via stimulation of integrin alphavbeta(3). Failure to degrade collagen-I critically impairs HSC apoptosis and may prevent the effective restoration of hepatocyte mass in liver fibrosis.
引用
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页码:47 / +
页数:24
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