Fibrosis Hepática: El papel de las metaloproteinasas y de TGF-β / Hepatic fibrosis: Role of matrix Metallopoteases and TGF-β

La fibrosis hepática involucra múltiples eventos celulares y moleculares que inducen un excesivo depósito de proteínas de matriz extracelular que distorsionan la arquitectura del parénquima hepático, cuya etapa final es conocida como cirrosis. El daño proviene de una variedad de causas como abuso de drogas y enfermedades virales, autoinmunes, metabólicas y colestásicas. La degradación de estas proteínas de matriz ocurre predominantemente como una consecuencia de la acción de metalopro teinasas (MMPs) que degradan sustratos colágenos y no colágenos. La degradación de la matriz en el hígado se lleva a cabo principalmente por la acción de cuatro de estas enzimas: MMP-1, MMP-2, MMP-3 y MMP-9. En el sistema fibrinolítico, las MMPs pueden ser activadas a través de un corte proteolítico por acción del activador de plasminógeno tipo urocinasa y un segundo mecanismo de activación es realizado por las mismas MMPs. La regulación para restringir la actividad puede ser a diferentes niveles; en el sistema fibrinolítico el principal regulador es el PAI- 1, molécula que bloquea la conversión de plasminógeno a plasmina y la MMP no puede ser activada. Un segundo nivel de inhibición es posible a través del TIMP, que inhibe la actividad proteolítica aun cuando las MMPs hayan sido activadas vía plasmina. Durante condiciones patológicas la sobreexpresión de estos inhibidores es dirigida por el factor de crecimiento transformante β, el cual en un padecimiento fibrótico actúa como el más importante factor adverso.

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 metalloproteinases (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 metalloproteinases. 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 proteolytic 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-β that in a fibrotic disease acts as an extremely important adverse factor.

A study of the interaction between Helicobacter pylori and components of the human fibrinolytic system

The interaction of plasminogen, tissue plasminogen activator (t-PA) and urokinase with a clinical strain of Helicobacter pylori was studied. Plasminogen bound to the surface of H. pylori cells in a concentration-dependent manner and could be activated to the enzymatic form, plasmin, by t-PA. Affinity chromatography assays revealed a plasminogen-binding protein of 58.9 kDa in water extracts of surface proteins. Surface-associated plasmin activity, detected with the chromogenic substrate CBS 00.65, was observed only when plasminogen and an exogenous activator were added to the cell suspension. The two physiologic plasminogen activators, t-PA and urokinase, were also shown to bind to and remain active on the surface of bacterial cells. epsilon-Aminocaproic acid caused partial inhibition of t-PA binding, suggesting that the kringle 2 structure of this activator is involved in the interaction with surface receptors. The activation of plasminogen by t-PA, but not urokinase, strongly depended on the presence of cells and a 25-fold enhancer effect on the initial velocity of activation by t-PA compared to urokinase was established. Furthermore, a relationship between cell concentration and the initial velocity of activation was demonstrated. These findings support the concept that plasminogen activation by t-PA on the bacterial surface is a surface-dependent reaction which offers catalytic advantages

Effect of growth hormone on fibrinolytic system in rat.

Growth hormone deficiency (GHD) is associated as a risk factor in increased mortality from cardiovascular diseases. Abnormal lipid profile and increased levels of plasminogen activator inhibitor (PAI) and fibrinogen have been noted in GHD patients. Present study was carried out to investigate the effect of growth hormone (GH) on plasminogen activator (PA) activity in heart, levels of PA, PAI, glucose and fibrinogen in plasma and serum lipid profile. Rats were injected 125 mU GH kg-1 body weight subcutaneously daily for one week. PA activity was significantly higher in the heart of GH treated rats as compared to controls. GH treatment decreased plasma glucose and fibrinogen levels significantly. No significant differences were seen in PA, PAI in plasma, triglycerides and total cholesterol in serum of the two groups of rats. A significant increase in high density lipoprotein cholesterol (HDL) occurred in GH treated group resulting into a decrease in LDL/HDL ratio. The results indicate that GH may be beneficial in cardiovascular diseases as it decreases the levels of plasma fibrinogen and increases the level of HDL in blood and also increases the level of PA in heart.

Plasminogen activation and breast cancer

Plasminogen activation is a widespread cellular mechanism for localized extracellular proteolysis that is postulated to participate in many diverse physiological and pathological phenomena. The present review in intended as an introduction to the subject, and is by no means comprehensive, except for the section on breast cancer. Seral extensive reviews are available that should be consulted by intersted readers (1-6).