Involvement of integrin‐linked kinase in carbon tetrachloride–induced hepatic fibrosis in rats
Involvement of integrin‐linked kinase in carbon tetrachloride–induced hepatic fibrosis in rats
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DOI：
10.1002/hep.21315
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发表时间：
2006-09
期刊：
影响因子：
13.5
通讯作者：
Yining Zhang;T. Ikegami;A. Honda;T. Miyazaki;B. Bouscarel;M. Rojkind;I. Hyodo;Y. Matsuzaki
中科院分区：
文献类型：
--
作者：
Yining Zhang;T. Ikegami;A. Honda;T. Miyazaki;B. Bouscarel;M. Rojkind;I. Hyodo;Y. Matsuzaki
整合素连接激酶（ILK）是一种多结构域粘着斑蛋白，参与整合素和生长因子受体之间的信号转导。虽然其表达在肺和肾纤维化中上调，但其在肝纤维化发展中的作用仍有待确定。因此，我们认为研究ILK是否参与肝星状细胞的活化并因此在肝纤维化的发展中起作用是重要的。从CCl 4诱导的肝硬化大鼠获得的肝脏切片的免疫组织化学分析显示，窦周区域的肝星状细胞中ILK和α平滑肌肌动蛋白的表达和共定位增加。此外，从纤维化肝脏分离的肝星状细胞表达高水平的ILK和α-平滑肌肌动蛋白，并且它们的表达在培养物中持续。相反，从正常大鼠肝脏中分离的肝星状细胞（HSC）不表达ILK，但当细胞在培养中被激活时，其表达增加。我们的研究还表明，ILK参与ERK 1/2、p38 MAPK、JNK和PKB的磷酸化，并且通过siRNA选择性抑制ILK表达导致其磷酸化的显著降低。这些变化伴随着细胞扩散和迁移的显著抑制，而不影响细胞增殖。总之，ILK在HSC活化中起关键作用，并可能成为抗纤维化治疗的可能靶点。（《肝脏学》2006年;44：612-622）
Integrin‐linked kinase (ILK) is a multidomain focal adhesion protein implicated in signal transduction between integrins and growth factor receptors. Although its expression is upregulated in pulmonary and renal fibrosis, its role in the development of hepatic fibrosis remains to be determined. Therefore, we considered it important to investigate whether ILK is involved in activation of hepatic stellate cells and thus plays a role in the development of hepatic fibrosis. Immunohistochemical analysis of liver sections obtained from rats with CCl4‐induced cirrhosis revealed increased expression and colocalization of ILK and alpha‐smooth muscle actin in hepatic stellate cells in perisinusoidal areas. In addition, hepatic stellate cells isolated from fibrotic livers expressed high levels of ILK and alpha‐smooth muscle actin, and their expression was sustained in culture. In contrast, hepatic stellate cells (HSCs) isolated from normal rat liver did not express ILK, but its expression was increased when the cells were activated in culture. Our studies also showed that ILK is involved in the phosphorylation of ERK 1/2, p38 MAPK, JNK, and PKB and that selective inhibition of ILK expression by siRNA results in a significant decrease in their phosphorylation. These changes were accompanied by significant inhibition of cell spreading and migration without affecting cell proliferation. In conclusion, ILK plays a key role in HSC activation and could be a possible target for antifibrogenic therapy. (HEPATOLOGY 2006;44:612–622.)