Estrés oxidativo hepatocitario y hepatopatía alcohólica. Hepatocyte oxidant stress and alcoholic liver disease. L. Conde de la Rosa, H. Moshage1 y N. Nieto. Hepatic stellate cells and alcoholic liver disease. Células estrelladas hepáticas y hepatopatía alcohólica. M. Vera and N. Nieto. Department of Medicine. Division. con hepatitis alcohólica Actualmente se reconoce a la esteatohepatitis como parte del espectro del hígado graso no alcohólico. (HGNA) la hepatopatía.

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Hepatic stellate cells and alcoholic liver disease. Division of Liver Diseases. Mount Sinai School of Medicine. Liver fibrosis represents a significant health problem worldwide for which no effective therapy exists. A great alcoholcia of research has been carried out to understand the molecular mechanisms responsible for the development of liver fibrosis.

Activated stellate cells are the primary cell type responsible for the production of collagen I, the key protein involved in the development of liver fibrosis. Excessive deposition of collagen I occurs along with impaired extracellular matrix remodeling. Following a fibrogenic stimulus stellate cells transform into an activated collagen type I-producing cell.

Numerous changes in gene expression are associated with stellate cell activation, including the induction of several intracellular signaling cascades, which help maintain the activated hepatopahia and control the fibrogenic and proliferative state of the cell.

Activation of stellate cells is mediated by factors released from alcoyolica and Kupffer cells as they produce reactive oxygen species, nitric oxide, cytokines, growth factors, and cyclooxygenase and lipoxygenase metabolites, which provide pivotal paracrine effects in the liver milieu.

Inhibition of stellate cell activation, proliferation, and the increased production of extracellular matrix i.

Liver fibrosis is the common consequence of chronic liver injury of wide etiology 1. Chronic alcohol abuse is the main reason for developing liver fibrosis and eventually cirrhosis, hepaopatia major cause of death worldwide 1,2. Fibrosis is characterized by excessive accumulation of extracellular matrix ECM proteins with very little degradation 1,2.

Estrés oxidativo hepatocitario y hepatopatía alcohólica

Advanced fibrosis disrupts the normal liver architecture, increases portal pressure, and impairs intercellular communication 3. In humans, collagen type I deposits are usually localized to the pericentral and perisinusoidal regions of the liver 2,4,5.

Prior to the onset of well established hepatic fibrosis, the liver usually becomes aocoholica and undergoes steatohepatitis 6. Many of the metabolic and toxic effects of alcohol in the liver have been associated with its metabolism because it generates toxic metabolites and induces a state of oxidative stress due to activation slcoholica CYP2E1, impairment of the mitochondrial function, and a decrease in glutathione stores A major pathway for ethanol metabolism is alcohol dehydrogenase ADH 8.

Acetaldehyde is then reduced to acetate, most of which is then secreted to the bloodstream 8. While most ethanol is oxidized by ADH when alcohol levels are low; cytochrome PE1 CYP2E1an ethanol inducible from in the microsomal compartment of hepatocytes and Kupffer cells, plays a more important role in ethanol oxidation at high concentrations of ethanol binge drinking and in chronic alcohol consumption chronic alcoholism CYP2E1 oxidizes ethanol to generate many toxic products, such as acetaldehyde, 1-hydroxyethyl radical, and other reactive oxygen species ROSsuch as superoxide radical O 2.

There is a considerable interest in the role of oxidative stress and ethanol generation of ROS in the mechanism by which ethanol is hepatotoxic Among the noxious effects of alcohol are: TNF a and TGF b 21,22 ; f induction of ‘leaky gut’ with translocation of bacterial-derived endotoxin LPSthe consequent activation of Kupffer cells, and the release of other soluble mediators and ROS 23,24 ; and g impairment of the antioxidant defense 17, All these effects enhance liver injury and contribute in one way or another to the activation of stellate cells HSC.



The normal liver contains an epithelial component hepatocytesan endothelial lining endothelial cellstissue macrophages Kupffer cellsnatural killer cells NKand perivascular mesenchymal cell, HSC, which are the key fibrogenic cells The cellular elements of the liver are organized within the sinusoid, with the subendothelial space of Disse separating the epithelium from the sinusoidal endothelium.

In normal liver this space contains a non electron-dense basement membrane-like matrix which is essential for maintaining the differentiated function of all resident liver cells As the liver becomes fibrotic, the total content of collagens and non-collagenous components increases and it is accompanied by a shift in the type of ECM in the subendothelial space from the normal low density basement membrane-like matrix to interstitial type matrix containing fibril-forming collagens mostly collagens I and III Their main function is storage and homeostasis of vitamin A and other retinoids, which are stored in cytoplasmic lipid droplets as retinyl esters 29, HSC regulate the sinusoidal blood flow, produce apolipoproteins, prostaglandins, growth factors, and cytokines all of which contribute to ECM homeostasis 29, Synthesis and degradation of normal hepatic ECM is essential for the integrity of the space of Disse and for the intra- and intercellular communication among neighboring cells 29, Following a fibrogenic stimulus, HSC undergo a complex process of activation in which they become transformed from quiescent to activated myofibroblast-like cells 8, Phenotypic changes include stretching, nuclear and cellular enlargement, cytoplasmic spreading, elongation of processes to establish contacts among cells, and loss of lipid droplets 26,29, As they become activated, HSC increase a -smooth muscle actin a -sma and collagen type I protein expression ,31they proliferate, and migrate to the site of injury where ECM builds up and scarring occurs The phenomenon of HSC activation takes place as a sequence of well interrelated events 26, The first steps encompass rapid changes in gene expression, associated with transcriptional events e.

COL1A1 and COL1A2 up-regulationand induction of immediate early genes, which render the cells responsive to cytokines and other local stimuli from paracrine or autocrine origin The subsequent steps incorporate the cellular events that amplify the activated phenotype through enhanced cytokine expression and responsiveness The perpetuation of HSC activation involves key phenotypic responses mediated by increased cytokine production and remodeling of ECM. These phenotypic responses of HSC include: A family of matrix-metalloproteinases MMPs contributes to either pathologic or restorative matrix degradation 37,41, MMPs can be either activated through proteolytic cleavage 43or inhibited by binding to specific inhibitors known as tissue inhibitors of metalloproteinases TIMPs Sustained TIMP-1 expression is emerging as a key reason why fibrosis progresses 48, Retinoids may be directly linked to fibrogenesis as they stimulate the activation of latent TGF b 1, thereby increasing its fibrogenic activity Chronic alcohol liver injury leads to fibrosis, with the subsequent disruption of the liver architecture, and impairment of hepatic metabolism 15, The cross-talk between parenchymal and non-parenchymal cells and the excessive production of ECM components are main features in the development of hepatic injury and fibrosis 38, Soluble factors, such as cytokines, chemokines, and ROS are candidate mediators for the induction of the fibrogenic response 26,32,40, Reactive nitrogen species may also play a role.

Hepatitis alcohólica – Síntomas y causas – Mayo Clinic

Perpetuation results form autocrine and paracrine stimulation, as well as from accelerated ECM remodeling 26,32, TGF- b is considered to be the heppatopatia potent pro-fibrogenic cytokine 35, It suppresses hepatocyte proliferation, stimulates HSC activation, promotes ECM production, and mediates hepatocyte apoptosis 3,35,53, ROS also modulate the binding of transcription factors e. Ethanol impairs gut permeability leading to overgrowth of Gram negative bacteria Endotoxin or lipopolysaccharide LPSa component of the Gram negative bacterial wall, translocates from the intestinal lumen into the portal circulation triggering Kupffer cell activation Influx of Kupffer cells coincides with the appearance of HSC activation markers e.


PDGFR b and a -sma Kupffer cells may stimulate matrix synthesis, cell proliferation, and release of retinoids by HSC through the actions of cytokines and reactive species These effects are enhanced under ethanol treatment, and a role for polyunsaturated fatty acids should be considered as critical components which promote injury in several in vitro and in vivo models of ethanol administration 85, Injury of sinusoidal endothelial cells by ROS and acetaldehyde stimulates the hepatoparia of certain fibronectin isoforms, such as leptin, which may activate HSC Moreover, damaged endothelial cells hepato;atia latent TGF- b 1 into its active form 22, Also, sinusoidal endothelial cells increase the expression of vascular endothelial growth factor VEGF in response to injury Activated HSC secrete inflammatory chemokines e.

An expanding family of matrix-metalloproteinases MMPs contributes to either pathologic or restorative matrix degradation 41, These enzymes fall into five categories based on substrate specificity: Metalloproteinases can be either activated through proteolytic cleavage, or inhibited by binding to specific inhibitors known as tissue inhibitors of metalloproteinases TIMPs Failure to degrade the accumulated scar is a major reason why fibrosis progresses to cirrhosis 7.

In humans, MMP-1 in rats, MMP is the main protease which degrades type I collagen, the principal collagenous protein in liver fibrosis alcoholkca More importantly, progressive fibrosis is associated with marked increases in TIMP-1 and TIMP-2 44,46leading to a net decrease in protease activity, and therefore matrix accumulation. HSC are the major source of these inhibitors 44, Alcohol consumption mediates suppression of the innate immunity as decreases NK cells activity and their numbers 99, Current questionable trends of thought suggest that reversion of fibrosis may happen by inducing apoptosis or necrosis of activated HSC, or less likely by transformation of activated HSC to a more quiescent phenotype.


Spontaneous resolution of experimental fibrosis is associated with the clearance of collagen type I-producing a -sma positive myofibroblasts activated HSC and transdifferentiated portal fibroblasts HSC clearance has been attributed to the induction of apoptosis One theoretical approach to reverse fibrosis is the reverse trans-differentiation of activated HSC to a more quiescent phenotype.

Expression of these transcription factors is lost in activated HSC Alcoholicx most efficient treatment for alcohol liver diseases is usually the cessation of the contributing agent e.

Although liver fibrosis is reversible, cirrhosis, the end-stage consequence of fibrosis, is generally irreversible. Thus, efforts to understand hdpatopatia focus primarily on events that lead to the early accumulation of scar e. Inhibition of HSC activation, proliferation, and the increased production of ECM are crucial steps for intervention in hepatic fibrogenesis.

Liver fibrosis-from bench to bedside. J Hepatol ; 38 Supl.

Bataller R, Brenner DA. J Clin Invest ; Chronic liver injury, TGF-beta, and cancer. Exp Mol Med ; Postgrad Med J ; Springer Semin Immunopathol ; The management of alcoholic liver disease. Molecular mechanisms of alcohol-induced hepatic fibrosis. Dig Dis ; Clin Liver Dis ; 9: Wu D, Cederbaum AI. Alcohol, oxidative stress, and free radical damage. Alcohol Res Health ; Effects of alcohol and oxidative stress on liver pathology: Alcohol Clin Exp Res ; Kessova I, Cederbaum AI.