Fibrillin-1 expression in normal and fibrotic rat liver and in cultured hepatic fibroblastic cells:: modulation by mechanical stress and role in cell adhesion
Fibrillin-1 expression in normal and fibrotic rat liver and in cultured hepatic fibroblastic cells:: modulation by mechanical stress and role in cell adhesion
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DOI：
10.1038/labinvest.3700023
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发表时间：
2004-02-01
影响因子：
5
通讯作者：
Desmoulière, A
中科院分区：
文献类型：
--
作者：
Lorena, D;Darby, IA;Desmoulière, A
原纤蛋白-1与弹性蛋白一起，是在整个细胞外空间发现的弹性纤维的主要成分，并且负责大多数组织和器官的生物力学性质。本研究探讨了在实验性大鼠肝纤维化和体外培养条件下，Escherin-1的表达和调控，并进一步分析了Escherin-1片段对细胞粘附的作用。肝纤维化的诱导，使大鼠胆总管结扎72小时和7天或四氯化碳（CCl 4）治疗2周和6周。免疫组化显示，胆管结扎后，胰蛋白酶-1，弹性蛋白，和α-平滑肌肌动蛋白共定位在发展中的门静脉结缔组织。在CCl 4处理的动物中，在隔膜中观察到类似的共定位;然而，在实质的活化α-平滑肌肌动蛋白阳性星状细胞周围未观察到弹性蛋白沉积。用促纤维化介质转化生长因子-β 1（TGF-β 1）治疗大大增加了培养的肝成纤维细胞的β 1蛋白表达。与生长在无限制的胶原晶格中的细胞相比，生长在受限制（应激）的胶原晶格中的细胞中的Escherin-1表达水平显著更高。细胞粘附在含有RGD序列（rF 6 H）的C-terminal片段上略有增加（在0.3和2.5 μ g/ml之间），并在较高浓度下降低，而粘附在C-terminal片段上（rF 16）呈剂量依赖性降低。此外，rF 16片段降低了细胞与纤连蛋白的粘附。总之，我们的研究说明了在两种不同的肝纤维化发生机制中发生的重要沉积。此外，TGF-β 1和机械应力诱导的β-淀粉样蛋白-1表达，以及β-淀粉样蛋白-1片段的抗粘附特性表明了组织重塑过程中生理和病理β-淀粉样蛋白-1 catalysts的重要意义。
Fibrillin-1, together with elastin, is the main component of elastic fibers found throughout the extracellular space and responsible for the biomechanical properties of most tissues and organs. In this work, fibrillin-1 expression and modulation were explored in experimental rat liver fibrosis and in vitro; furthermore, the role of fibrillin-1 fragments on cell adhesion was analyzed. Fibrosis was induced by subjecting rats to common bile duct ligation for 72 h and 7 days or carbon tetrachloride (CCl4) treatment for 2 and 6 weeks. Immunohistochemistry showed that, after bile duct ligation, fibrillin-1, elastin, and alpha-smooth muscle actin colocalized in the developing portal connective tissue. In CCl4-treated animals, a similar colocalization was observed in septa; however, elastin deposition was not observed around activated alpha-smooth muscle actin-positive stellate cells of the parenchyma. Treatment with the profibrogenic mediator transforming growth factor-beta1 (TGF-beta1) greatly increased the fibrillin-1 expression of cultured liver fibroblasts. The level of fibrillin-1 expression was significantly higher in cells grown in restrained (stressed) collagen lattices compared with those grown in unrestrained collagen lattices. Cell adhesion on the C-terminal fragment of fibrillin-1 containing the RGD sequence (rF6H) slightly increased (between 0.3 and 2.5 mug/ml) and decreased at higher concentrations, while adhesion on the IN-terminal fragment of fibrillin-1 (rF16) was dose-dependently decreased. In addition, the rF16 fragment decreased cell adhesion to fibronectin. In conclusion, our study illustrates the important deposition of fibrillin-1 that occurs in two mechanistically distinct settings of liver fibrogenesis. Furthermore, the induction of fibrillin-1 expression by TGF-beta1 and mechanical stress, and the antiadhesive properties of fibrillin-1 fragments suggest important implications for physiological and pathological fibrillin-1 catabolism during tissue remodeling.