Review Article
Oxidative damage and fibrogenesis

https://doi.org/10.1016/S0891-5849(96)00327-9Get rights and content

Abstract

Various chronic disease processes are characterized by progressive accumulation of connective tissue undergoing fibrotic degeneration. Evidence of oxidative reactions is often associated with fibrogenesis occurring in liver, lung, arteries, and nervous system. Moreover, an increasing bulk of experimental and clinical data supports a contributory role of oxidative stress in the pathogenesis of this kind of disease. Indeed, many etiological agents of fibrogenesis stimulate free radical reactions either directly or through inflammatory stimuli. Free radicals, as well as products of their reaction with biomolecules, appear to modulate the activity of the two cellular types mainly involved in the process, namely phagocytes and extracellular matrix-producing cells. Lipid peroxidation and certain lipid peroxidation products induce genetic overexpression of fibrogenic cytokines, the key molecules in the pathomechanisms of fibrosis, as well as increased transcription and synthesis of collagen. Both these events can be downregulated, at least in experimental models, by the use of antioxidants. The effect of oxidative stress on cytokine gene expression appears to be an important mechanism by which it promotes connective tissue deposition. Copyright © 1996 Elsevier Science Inc.

Introduction

Increased deposition of collagen and other extracellular matrix proteins is a feature of many chronic diseases affecting the liver, lung, arteries, and nervous system. In studies of the pathogenesis of tissue fibrosis, particular attention has been paid quite recently to its frequent association with enhanced lipid peroxidation and/or deranged antioxidant defensive system.

The oxidative breakdown of membrane lipids can be initiated by a variety of free radicals and is characterized, during the propagation of the process, by increased generation of both reactive oxygen species (ROS) and organic radical intermediates.1, 2 This free radical-mediated process is often implicated in the change of the intracellular oxidation-reduction balance toward oxidation, commonly defined as biochemical oxidative stress.[3]

Increasing numbers of reports are suggesting a different role of lipid peroxidation, as well as other mechanisms of oxidative stress, in physiopathology; such a role depends on the extent of oxidative stress. Marked oxidative derangement of cell structure and function is known to be able, by various mechanisms, to exert irreversible damage.4, 5 On the other hand, for instance, a moderate oxidative imbalance has been shown to stimulate liver protein kinase C6, 7 and human skin fibroblast proliferation;[8] consistently, low amounts of lipid peroxidation end products have been found to upregulate several enzymatic activities and to display chemotactic action.9, 10 Hence, consideration is now being given to a possible modulatory role of a low- to medium-cellular oxidative unbalance in processes such as inflammation and fibrosis (Fig. 1).

Critical analysis of the various chronic conditions characterized by fibrogenesis appeared to be timely, to evaluate the contribution of oxidative stress to pathogenesis. Evidence of the involvement of certain reactive free radicals or derived molecules in the different chronic pathologies was first considered; subsequently, cellular types as well as biochemical mechanisms involved in fibrogenesis were analyzed with the aim of elucidating potential ways in which reactive oxidant species act as modulators. Finally, particular attention was paid to the possible interference, by oxidative stress, with gene expression of fibrogenic cytokines, key molecules in the progression of fibrotic tissue degeneration.

Section snippets

Evidence of oxidative stress and lipid peroxidation in clinical and experimental chronic conditions of increased connective tissue deposition

The involvement of free radical-mediated reactions has been reported for several clinical or experimental diseases caused by chronic exposure to etiological agents or by inherited defects, both of which are able to perpetuate inflammatory response with increased deposition of collagens and other extracellular matrix proteins. Both the list of these free radical-related fibrotic diseases and their specific biomedical interest are on the increase. We thus reviewed the most recent results

Chronic fibro-proliferative diseases: The central role of macrophages and extracellular matrix-producing cells

Chronic fibrotic diseases can differ from each other in etiology, natural history, clinical signs, and symptoms. But, in terms of pathogenesis, they share some basic common features. For instance, at first sight, three serious chronic diseases—h̃erosclerosis, pulmonary fibrosis, and liver fibrosis—may appear very different in their development.12, 13, 14, 137, 150, 151, 152 In all three, though, a central, and indeed an essential, role is played by macrophages and by extracellular

Pathogenetic mechanisms that may link ROS generation, onset of lipid peroxidation, and increased deposition of collagen and extracellular matrix

How can an increased steady-state level of reactive oxygen species interfere with the activity of the various cells actually involved in inflammation and fibrosis? A well-established concept, possibly relevant in fibro-proliferative diseases, is that ROS, such as superoxide anion and hydrogen peroxide as well as other free radicals, pro-oxidant compounds, and aldehydic end products of lipid peroxidation, can modulate cell proliferation, possibly by operating along cell signaling pathways known

Conclusions

The association of intracellular unbalanced redox equilibrium with excessive extracellular matrix deposition is a common event in chronic inflammatory processes taking place in the different tissues and organs. A growing bulk of evidence actually supports a causative role of oxidative stress in fibrotic degeneration of tissues and organs.

The involvement of two kinds of cells, macrophages and (myo)fibroblast-like cells in the fibrogenic processes occurring in various organs can be clearly

Acknowledgements

This study was supported by the Ministero dell'Università e della Ricerca Scientifica e Tecnologica, Progetto Nazionale Cirrosi Epatica ed Epatiti Virali, and Progetto Nazionale Radicali Liberi ed Equilibrio Redox, Rome, Italy. Financial support was also provided by the Consiglio Nazionale delle Ricerche, Progetto Finalizzato Applicazione Clinica della Ricerca Oncologica, and Progetto Finalizzato Invecchiamento, Rome, Italy and by the Associazione Italiana per la Ricerca sul Cancro.

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