ABSTRACT
Uncontrolled production of collagen I is the main feature of liver fibrosis. Following a fibrogenic stimulus such as alcohol, hepatic stellate cells (HSC) transform into an activated collagen-producing cell. In alcoholic liver disease, numerous changes in gene expression are associated with HSC activation, including the induction of several intracellular signaling cascades, which help maintain the activated phenotype and control the fibrogenic and proliferative state of the cell. Detailed analyses for understanding the molecular basis of the collagen I gene regulation have revealed a complex process involving reactive oxygen species (ROS) as key mediators. Less is known, however, about the contribution of reactive nitrogen species (RNS). In addition, a series of cytokines, growth factors, and chemokines, which activate extracellular matrix (ECM)-producing cells through paracrine and autocrine loops, contribute to the fibrogenic response.
Subject(s)
Collagen Type I/metabolism , Liver Cirrhosis/metabolism , Oxidative Stress , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Autocrine Communication , Collagen Type I/genetics , Extracellular Matrix/metabolism , Gene Expression Regulation , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Humans , Liver Cirrhosis/pathology , Liver Cirrhosis, Alcoholic/metabolism , Metalloproteases/metabolism , Paracrine Communication , Signal TransductionABSTRACT
Acute and chronic alcohol consumption increases the production of reactive oxygen species (ROS), and enhances lipid peroxidation of lipids, proteins, and DNA. The mechanism by which alcohol causes cell injury is still not clear but a major role for ROS and lipid peroxidation-end products is considered. Many pathways have been suggested to play a role on how ethanol induces a state of "oxidative stress", including redox-state changes, acetaldehyde production, damage to the mitochondria, membrane injury, apoptosis, ethanol-induced hypoxia, effects on the immune system and altered cytokine production, increased endotoxin levels and activation of Kupffer cells, mobilization of iron, changes in the antioxidant defense, particularly mitochondrial glutathione (GSH), one electron oxidation of ethanol to 1-hydroxy-ethyl radical, and induction of CYP2E1. These pathways are not exclusive of one another and it is likely that several, indeed many systems contribute to the ability of ethanol to induce a state of oxidative stress.
Subject(s)
Hepatocytes/metabolism , Liver Diseases, Alcoholic/metabolism , Apoptosis , Cell Survival , Humans , Liver Diseases, Alcoholic/pathology , Reactive Oxygen Species/metabolismABSTRACT
El consumo agudo y crónico de alcohol aumenta la producciónde especies de oxígeno reactivas (EOR) y potencia la peroxidaciónde los lípidos, las proteínas y el ADN. El mecanismo por el que elalcohol produce lesión celular sigue sin estar claro, pero se piensaque las EOR y los productos de la peroxidación lipídica intervienende forma decisiva. Se ha señalado la intervención de muchasvías en la manera que tiene el etanol de inducir un estado de estrésoxidativo, incluidos los cambios de estado redox, la producciónde acetaldehído, el daño mitocondrial, las lesiones membranosas,la apoptosis, la hipoxia inducida por etanol, los efectossobre el sistema inmunitario y la producción alterada de citocinas,el aumento de los niveles de endotoxinas y de activación de las célulasde Kupffer, la movilización del hierro, la modulación de ladefensa antioxidante, especialmente del glutatión mitocondrial(GSH), la oxidación monoelectrónica del etanol a un radical 1-hidroxi-etilo y la inducción de la CYP2E1. Estas vías no son excluyentesentre sí y es probable que sean varios, ciertamente muchos,los sistemas que contribuyan a la capacidad que posee eletanol de inducir un estado de estrés oxidativo
Acute and chronic alcohol consumption increases the productionof reactive oxygen species (ROS), and enhances lipid peroxidationof lipids, proteins, and DNA. The mechanism by which alcoholcauses cell injury is still not clear but a major role for ROSand lipid peroxidation-end products is considered. Many pathwayshave been suggested to play a role on how ethanol induces a stateof oxidative stress, including redox-state changes, acetaldehydeproduction, damage to mitochondria, membrane injury, apoptosis,ethanol-induced hypoxia, effects on the immune system andaltered cytokine production, increased endotoxin levels and activationof Kupffer cells, mobilization of iron, modulation of the antioxidantdefense, particularly mitochondrial glutathione (GSH),one electron oxidation of ethanol to 1-hydroxy-ethyl radical, andinduction of CYP2E1. These pathways are not exclusive of oneanother and it is likely that several, indeed many, systems contributeto the ability of ethanol to induce a state of oxidative stress
