[Hepatic fibrosis: role of matrix metalloproteases and TGFbeta].
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.
Sentíes-Gómez
María Daniela
MD
Instituto de Biología Molecular y Terapia Génica, CUCS, Universidad de Guadalajara, Mexico.
Gálvez-Gastélum
Francisco Javier
FJ
Meza-García
Eduardo
E
Armendáriz-Borunda
Juan
J
D000328:Adult; D000818:Animals; D004789:Enzyme Activation; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D005544:Forecasting; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*
D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D010958:Plasminogen; D010960:Plasminogen Activators; D005341:Fibrinolysin; D020782:Matrix Metalloproteinases