Sentíes-Gómez María Daniela, Gálvez-Gastélum Francisco Javier, Meza-García Eduardo, Armendáriz-Borunda Juan
Instituto de Biología Molecular y Terapia Génica, CUCS, Universidad de Guadalajara, Mexico.
Gac Med Mex. 2005 Jul-Aug;141(4):315-22.
Liver fibrosis and cirrhosis involve multiple cellular and molecular events that lead to deposition of an excess of extracellular matrix proteins and increase the distortion of normal liver architecture. Etiologies include chronic viral hepatitis, alcohol abuse and drug toxicity. Degradation of these matrix proteins occurs predominantly as a result of a family of enzymes called metalloproteases (MMPs) that specifically degrade collagenous and non-collagenous substrates. Matrix degradation in the liver is due to the action of at least four of these enzymes: MMP-1, MMP-2, MMP-3 and MMP-9. In the fibrinolytic system, MMPs can be activated through proteolytic cleavage by the action of urokinase plasminogen activator; a second mechanism includes the same metalloproteases. This activity is regulated at many levels in the fibrinolytic system. The main regulator is the PAI-1. This molecule blocks the conversion of plasminogen into plasmin, and the MMP cannot be activated. At a second level, the inhibition is possible by binding to inhibitors called TIMP that can inhibit the proteolitic activity even when the MMPs had been previously activated by plasmin. During abnormal conditions, overexpression of these inhibitors is directed by the transforming growth factor-beta that in a fibrotic disease acts as an extremely important adverse factor.
肝纤维化和肝硬化涉及多个细胞和分子事件，这些事件导致细胞外基质蛋白过度沉积，并加剧正常肝脏结构的变形。病因包括慢性病毒性肝炎、酒精滥用和药物毒性。这些基质蛋白的降解主要是由一类称为金属蛋白酶（MMPs）的酶引起的，这类酶能特异性地降解胶原和非胶原底物。肝脏中的基质降解是由至少四种这类酶的作用导致的：MMP-1、MMP-2、MMP-3和MMP-9。在纤溶系统中，MMPs可通过尿激酶型纤溶酶原激活剂的蛋白水解作用被激活；第二种机制涉及相同的金属蛋白酶。这种活性在纤溶系统的多个层面受到调节。主要调节因子是PAI-1。该分子可阻止纤溶酶原转化为纤溶酶，从而无法激活MMPs。在第二个层面，可通过与称为TIMP的抑制剂结合来实现抑制作用，即使MMPs先前已被纤溶酶激活，TIMP也能抑制其蛋白水解活性。在异常情况下，这些抑制剂的过表达由转化生长因子-β调控，在纤维化疾病中，转化生长因子-β是一个极其重要的不利因素。
