Dynamics of elastin in liver fibrosis: Accumulates late during progression and degrades slowly in regression
Dynamics of elastin in liver fibrosis: Accumulates late during progression and degrades slowly in regression
复制标题
肝纤维化中弹性蛋白的动态：在进展过程中积累并在消退过程中缓慢降解。
DOI：
10.1002/jcp.28827
复制
发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
You, Hong
中科院分区：
文献类型：
--
作者：
Chen, Wei;Yan, Xuzhen;You, Hong
弹性蛋白是一种对弹性蛋白酶降解具有高度抗性的无定形蛋白，被认为是细胞外基质（ECM）成员中最稳定的组分。因此，在晚期肝纤维化中弹性蛋白的过度沉积可能有助于疾病可逆性的下降。我们前期的研究发现，抑制弹性蛋白交联可以有效地阻止肝纤维化的进展。为了进一步了解弹性蛋白在肝纤维化中的作用，我们基于动态和双向CCl 4诱导的肝纤维化小鼠模型系统地研究了弹性蛋白的表达、积累和降解，并观察了培养的LX-2细胞中弹性蛋白球的超微结构。我们发现，在肝纤维化进展和消退过程中，原弹性蛋白（可溶性弹性蛋白）和胶原蛋白I的表达模式在转录和转录后水平上并不完全可比。在肝纤维化晚期，弹性蛋白主要聚集在结节间纤维间隔和扩大的汇管区，并与I型胶原交织在一起。通过共聚焦免疫荧光结合生化分析对弹性蛋白和胶原蛋白I进行的三维分析显示，就胶原蛋白而言，弹性蛋白沉积的特征在于进展中的晚期聚集和消退中的缓慢转换。此外，我们观察了肝纤维化和纤维溶解过程中ECM纤维的动态超微结构以及弹性蛋白原交联自聚集的弹性蛋白球的超微结构。我们目前的研究建立了进行性和消退性肝纤维化中弹性蛋白水平和形式的新的一般标志，并为进一步实验研究弹性蛋白在肝纤维化消退中的作用提供了基础。
Elastin is an amorphous protein highly resistant to elastase degradation and is believed to be the most stable component among the extracellular matrix (ECM) members. Thus the excessive deposition of elastin in advanced liver fibrosis may contribute to the declining reversibility of the disease. Our previous study has found that elastin crosslinking inhibition can effectively arrest liver fibrosis progression. To further understand the roles of elastin involved in liver fibrosis, we systematically investigated the expression, accumulation, and degradation based on dynamic and bidirectional CCl4‐induced liver fibrosis mouse models and visualized the ultrastructure of elastin globules in cultured LX‐2 cells. We found that the expression pattern of tropoelastin (soluble elastin) and collagen I was not completely comparable at both the transcriptional and posttranscriptional levels during liver fibrosis progression and regression. Elastin mainly accumulated onto the internodular fibrous septa and enlarged portal areas and intertwined with collagen I at the late stage of liver fibrosis. Three‐dimensional analysis of elastin and collagen I by confocal immunofluorescence coupled with biochemical analyses revealed that with respect to collagen, elastin deposition was characterized by late aggregation in progression and slow turnover in regression. In addition, we visualized the dynamic ultrastructure of ECM fibers during liver fibrogenesis and fibrolysis and the ultrastructure of elastin globules self‐aggregated by tropoelastin crosslinking. Our current study established new general hallmarks of elastin levels and forms in progressive and regressive liver fibrosis and provided a foundation for further experimental investigation of the growing role of elastin in liver fibrosis regression.