Spontaneous recovery from micronodular cirrhosis: Evidence for incomplete resolution associated with matrix cross-linking
Spontaneous recovery from micronodular cirrhosis: Evidence for incomplete resolution associated with matrix cross-linking
复制标题
DOI：
10.1053/j.gastro.2004.03.009
复制
发表时间：
2004-06-01
期刊：
影响因子：
29.4
通讯作者：
Iredale, JP
中科院分区：
文献类型：
--
作者：
Issa, R;Zhou, XY;Iredale, JP
背景与目的：肝纤维化和肝硬化是由肝星状细胞（hepatic stellate cells，HSC）过度分泌基质蛋白引起的。以前被认为是不可逆的，我们研究了肝硬化模型，以确定介导和限制自发恢复的机制。方法：四氯化碳（CCl_4）中毒12周后，诱导大鼠肝硬化模型。在长达366天的自发恢复期间，分析肝脏的基质降解、基质金属蛋白酶（MMP）和金属蛋白酶组织抑制剂（TIMP）表达、星状细胞凋亡、组织转氨酶（tTg）表达和基质交联的证据。结果：经过366天的恢复，小结节性肝硬化发生了显著的重塑，成为大结节性肝硬化。在肝纤维化重塑过程中，肝组织中1型胶原和TIMP mRNA表达明显下降，MMPs呈活跃状态。消退的特征还在于HSC的凋亡，主要是在纤维化间隔的边缘。残留的隔膜，在366天没有重塑，其特征在于TG介导的交联和相对细胞减少。结论：从相对晚期的肝硬化中恢复是可能的，并导致从小结节性肝硬化到大结节性肝硬化的重塑。我们建议决议是有限的TG介导的基质交联和失败的HSC凋亡。
Background & Aims: Liver fibrosis and cirrhosis result from the excessive secretion of matrix proteins by hepatic stellate cells (HSCs). Previously considered irreversible, we have studied a model of cirrhosis to determine the mechanisms mediating and limiting spontaneous recovery. Metho : A micronodular cirrhosis was induced in rats after 12 weeks of CCl4 intoxication. Livers were analyzed for evidence of matrix degradation, matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression, stellate cell apoptosis, tissue transglutaminase (tTg) expression, and matrix cross-linking during spontaneous recovery of up to 366 days. Results: Over 366 days of recovery, micronodular cirrhosis underwent significant remodeling to a macronodular cirrhosis. Expression of collagen-1 and TIMP messenger RNA (mRNA) decreased significantly and active MMPs were shown in livers during remodeling of fibrosis. Resolution also was characterized by apoptosis of HSCs, predominantly at the margins of fibrotic septa. Residual septa, not remodeled at 366 days, were characterized by tTg-mediated cross-linking and relative hypocellularity. Conclusion: Recovery from comparatively advanced cirrhosis is possible and results in remodeling from a micronodular cirrhosis to a macronodular cirrhosis. We suggest resolution is limited by tTg-mediated matrix cross-linking and a failure of HSC apoptosis.