Alcoholic liver disease and the potential role of plasminogen activator inhibitor-1 and fibrin metabolism.
Alcoholic liver disease and the potential role of plasminogen activator inhibitor-1 and fibrin metabolism.
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DOI：
10.1258/ebm.2011.011255
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Arteel GE
中科院分区：
文献类型：
--
作者：
Beier JI;Arteel GE
纤溶酶原激活物抑制剂-1 （PAI-1）由于其抑制纤溶酶原激活物的经典作用而在纤溶中起主要作用。虽然纤维蛋白溶解增加在酒精性肝硬化中很常见，但纤维蛋白溶解减少（主要由PAI-1水平升高引起）在酒精性肝病（ALD）的发展过程中很常见。然而，PAI-1是否在早期ALD的发展中起因果作用尚不清楚。最近在实验模型中的研究表明，PAI-1可能有助于ALD的早期（脂肪变性）、中期（脂肪性肝炎）和晚期（纤维化）阶段的发展。例如，急性和慢性乙醇引起的脂肪肝都被PAI-1的遗传抑制所钝化。这种靶向PAI-1的作用似乎至少部分是由极低密度脂蛋白（VLDL）合成的增加介导的，因为这种急性期蛋白在遗传上缺乏。采用乙醇和脂多糖管理的双重打击模型的结果表明，PAI-1在肝脏炎症中起关键作用，很可能是由于它能够引起纤维蛋白积累，随后使肝脏对随后的破坏性损伤敏感。最后，PAI-1在肝纤维化中的作用尚不清楚，似乎PAI-1在这种病理变化中可能具有双重作用，既具有保护性（增强再生）又具有破坏性（阻止基质降解）。综上所述，这些研究结果表明PAI-1可能在ALD的各个阶段发挥多重作用，既有保护作用，也有损害作用。后一种作用是通过其对脂肪变性（即降低VLDL合成）、炎症（即损害纤维蛋白溶解）和纤维化（即减弱基质降解）的影响介导的，而前者是通过在损伤后维持肝细胞分裂介导的。
Plasminogen activator inhibitor-1 (PAI-1) is a major player in fibrinolysis due to its classical role of inhibiting plasminogen activators. Although increased fibrinolysis is common in alcoholic cirrhosis, decreased fibrinolysis (driven mostly by elevated levels of PAI-1) is common during the development of alcoholic liver disease (ALD). However, whether or not PAI-1 plays a causal role in the development of early ALD was unclear. Recent studies in experimental models have suggested that PAI-1 may contribute to the development of early (steatosis), intermediate (steatohepatitis) and late (fibrosis) stages of ALD. For example, fatty liver owing to both acute and chronic ethanol was blunted by the genetic inhibition of PAI-1. This effect of targeting PAI-1 appears to be mediated, at least in part, by an increase in very low-density lipoprotein (VLDL) synthesis in the genetic absence of this acute phase protein. Results from a two-hit model employing ethanol and lipopolysaccharide administration suggest that PAI-1 plays a critical role in hepatic inflammation, most likely due to its ability to cause fibrin accumulation, which subsequently sensitizes the liver to ensuing damaging insults. Lastly, the role of PAI-1 in hepatic fibrosis is less clear and appears that PAI-1 may serve a dual role in this pathological change, both protective (enhancing regeneration) and damaging (blocking matrix degradation). In summary, results from these studies suggest that PAI-1 may play multiple roles in the various stages of ALD, both protective and damaging. The latter effect is mediated by its influence on steatosis (i.e. decreasing VLDL synthesis), inflammation (i.e. impairing fibrinolysis) and fibrosis (i.e. blunting matrix degradation), whereas the former is mediated by maintaining hepatocyte division after an injury.
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DOI：
10.1124/jpet.107.122069
发表时间：
2007-08
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
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通讯作者：
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影响因子：
29.4
作者：
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影响因子：
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影响因子：
3.8
作者：
Bajt, Mary Lynn;Yan, Hui-Min;Jaeschke, Hartmut
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影响因子：
2.3
作者：
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