ReviewOxidative stress-related molecules and liver fibrosis
Introduction
Liver fibrosis can be considered as a dynamic and highly integrated cellular response to chronic liver injury [1]. Whatever the etiology, the evolution of chronic liver disease (CLD) is characterized by perpetuation of parenchymal necrosis, chronic hepatitis and qualitative as well as quantitative alterations in extracellular matrix (ECM) composition, whereas activation of hepatic stellate cells (HSC) and involvement of macrophages and Kupffer cells predominate at cellular level [1], [2], [3]. At the molecular level, growth factors, cytokines and chemokines, changes in ECM organization and composition as well as reactive molecules originated by oxidative stress have been suggested to play a pathogenetic role [1], [2], [3]. Evidence of oxidative stress has been detected in almost all the clinical and experimental conditions of CLD with different etiology and fibrosis progression rate (Table 1 and Refs. [4], [5], [6]), often in association with decreased antioxidant defenses. As already proposed for atherosclerosis [7] and chronic degenerative diseases of CNS [8], oxidative stress-related molecules may act as mediators able to modulate tissue and cellular events responsible for the progression of liver fibrosis [1], [3], [4], [5], [6]. This review will highlight major concepts and recent insights in the field, and the definition ‘oxidative stress-related molecules’ will be used to indicate reactive oxygen intermediates (ROI, i.e. oxygen-centered free radicals or intermediates) as well as aldehydes from lipid peroxidation (i.e. a major feature of hepatic oxidative stress). Major concepts and findings related to the role of nitric oxide (NO) and reactive nitrogen oxide intermediates (RNOI) in chronic liver injury, with special reference to NO interactions with ROI and potential antifibrogenic action of NO, will be also presented.
Section snippets
Oxidative stress in CLD: basic and clinically relevant concepts
The term oxidative stress has been often employed to indicate the outcome of oxidative damage to biologically relevant macromolecules such as nucleic acids, proteins, lipids and carbohydrates [9]. This occurs when oxidative stress-related molecules, generated in the extracellular environment or within the cell, exceed cellular antioxidant defenses and, in the past, this aspect has been mainly related to the potential cytotoxic consequences of oxidative stress. At present this definition has
ROI and HAKs as cytotoxic agents: necrosis versus apoptosis, a matter of concentration?
Parenchymal liver necrosis and its perpetuation is a common condition in the natural history and progression of CLD [1], [2], [3]. Severe oxidative stress, considered a major cause of liver necrosis (i.e. acute liver injury), can be elicited by several pro-oxidants and hepatotoxic agents or drugs, leading to steady state concentrations of approx. 0.15 μM for H2O2 and 0.25 μM for total ROI [13] as well as 10−5 M for HNE and HAKs [12]. In addition, oxidative stress constitutes a key feature of
ROI and HAKs as pro-fibrogenic biological signals in the liver: the present and the future
The progression of fibrosis in CLD of different etiology is, at least in part, sustained by the activation and phenotypical modulation of HSC towards the so-called myofibroblast-like phenotype [1], [2], [3]. This process follows a relatively well defined and programmed temporal sequence that recognizes early (initiation or pre-inflammatory stage) and late events (perpetuation of HSC activation) in which the activated phenotype is fully expressed [1]. Phenotypic responses of activated HSC
NO and RNOI: cytoprotective, cytotoxic and signal intermediates in liver injury
Nitric oxide (NO) is a short-lived gaseous free radical known to exert many actions in the liver as well as in other tissues and organs [15]. In this review only major concepts, potentially relevant in conditions of CLD, with special reference to interactions with ROI at molecular level and effects at cellular level (particularly those on activated HSC), will be summarized [60], [61].
Antioxidants as potential therapeutics?
Several experimental reports have stated that antioxidant treatment in vivo is effective in preventing or reducing liver fibrosis. Liver fibrosis induced by chronic ethanol consumption is prevented by polyenylphosphatidylcholine (PPC), CYP2E1 inhibitors such as diallylsulfide (DAS) or phenylethylisothiocyanate (PIC) as well as by S-adenosyl-methionine (SAMe, used to replenish GSH levels) (reviewed in Refs. [19], [20]). SAMe is effective also in animal models [71] and positive results have been
Conclusions
Current literature indicate that ROI, HAKs and NO (including RNOI) are likely to be involved in the progression of liver fibrosis during CLD of different etiology. They may contribute to such progression by eliciting cytotoxicity or, more likely, by modulating tissue events and the functional response of potential target cells, particularly HSC phenotypic responses, but several possible aspects of their intervention, known to operate in other diseases [7], [8], still remain to be explored.
Acknowledgements
This work has been supported by Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST, Rome, Italy), National Project on Molecular and Cellular Biology of Hepatic Fibrosis. The authors are sincerely indebted to Professor Mario Umberto Dianzani for his continuous support and encouragement throughout the years.
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