Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis.
Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis.
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DOI：
10.1002/hep.23186
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发表时间：
2009-11
期刊：
影响因子：
13.5
通讯作者：
Rippe, Richard A.
中科院分区：
文献类型：
--
作者：
Son, Gakuhei;Hines, Ian N.;Lindquist, Jeff;Schrum, Laura W.;Rippe, Richard A.
肝星状细胞（HSC）是肝脏中负责纤维化期间过量胶原沉积的主要细胞类型。在纤维化刺激后，细胞从静止的维生素A储存细胞变为与细胞外基质合成增加和细胞增殖增加相关的活化细胞类型。磷脂酰肌醇3-激酶（PI 3 K）信号通路已被证明在体外调控HSC活化的几个方面，包括胶原合成和细胞增殖。使用靶向方法特异性抑制HSC中的PI 3 K信号传导，我们使用啮齿动物肝纤维化模型研究了PI 3 K在HSC中的作用。生成了在平滑肌α-肌动蛋白（αSMA）启动子控制下表达PI 3 K显性阴性形式的腺病毒（Ad-SMadnPI 3 K）。用Ad-SMAdnPI 3 K转导HSC导致增殖、迁移、胶原蛋白表达和几个额外的促纤维化基因减少，同时也促进细胞死亡。PI 3 K信号传导的抑制也与Akt、p70 S6 K和细胞外调节激酶（ERK）信号传导的活化减少以及细胞周期蛋白D1表达减少相关。胆管结扎后给予小鼠Ad-SMAdnPI 3 K导致HSC活化减少和细胞外基质沉积减少，包括胶原蛋白表达。还观察到促纤维化介质减少，包括肿瘤生长因子- β（TGF-β）、金属蛋白酶组织抑制剂-1（TIMP-1）和结缔组织生长因子（CTGF）。然而，通过丙氨酸氨基转移酶（ALT）水平评估的肝损伤并未减少。在活跃的纤维发生期间抑制HSC中的PI 3 K信号传导抑制细胞外基质（ECM）沉积，包括I型胶原的合成，并减少促纤维发生因子的表达。这些数据表明，靶向HSC中的PI 3 K信号传导可能代表肝纤维化的有效治疗靶点。
The hepatic stellate cell (HSC) is the primary cell type in the liver responsible for excess collagen deposition during fibrosis. Following a fibrogenic stimulus, the cell changes from a quiescent vitamin A storing cell to an activated cell type associated with increased extracellular matrix synthesis and increased cell proliferation. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been shown to regulate several aspects of HSC activation in vitro, including collagen synthesis and cell proliferation. Using a targeted approach to inhibit PI3K signaling specifically in HSCs, we investigated the role of PI3K in HSCs using a rodent model of hepatic fibrosis. An adenovirus expressing a dominant negative form of PI3K under control of the smooth muscle α-actin (αSMA) promoter was generated (Ad-SMAdnPI3K). Transducing HSCs with Ad-SMAdnPI3K resulted in decreased proliferation, migration, collagen expression, and several additional profibrogenic genes, while also promoting cell death. Inhibition of PI3K signaling was also associated with reduced activation of Akt, p70S6K, and extracellular regulated kinase (ERK) signaling as well as reduced cyclin D1 expression. Administering Ad-SMAdnPI3K to mice following bile duct ligation resulted in reduced HSC activation and decreased extracellular matrix deposition, including collagen expression. A reduction in profibrogenic mediators, including tumor growth factor – β (TGF-β), tissue inhibitor of metalloproteinase – 1 (TIMP-1), and connective tissue growth factor (CTGF) was also noted. However, liver damage, assessed by alanine aminotransferase (ALT) levels, was not reduced. Inhibition of PI3K signaling in HSCs during active fibrogenesis inhibits extracellular matrix (ECM) deposition, including synthesis of type I collagen, and reduces expression of profibrogenic factors. These data suggest that targeting PI3K signaling in HSCs may represent an effective therapeutic target for hepatic fibrosis.
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影响因子：
29.4
作者：
Marra, F;Gentilini, A;Gentilini, P
通讯作者：
Gentilini, P
影响因子：
25.7
作者：
Di Sario, A;Baroni, GS;Benedetti, A
通讯作者：
Benedetti, A
DOI：
10.1152/ajpgi.2000.279.1.g7
发表时间：
2000-07-01
影响因子：
4.5
作者：
Eng, FJ;Friedman, SL
通讯作者：
Friedman, SL
影响因子：
15.9
作者：
Bataller, R;Schwabe, RF;Brenner, DA
通讯作者：
Brenner, DA
影响因子：
4.8
作者：
Gäbele, E;Reif, S;Rippe, RA
通讯作者：
Rippe, RA