Iron-induced oxidant stress in alcoholic liver fibrogenesis

Abstract

Iron is an essential micronutrient. However, because human beings have no means to control iron excretion, excess iron, regardless of the route of entry, accumulates in parenchymal organs and threatens cell viability. Indeed, when iron-buffering capability is overwhelmed, oxidative stress–induced cell damage and fibrogenesis may arise, mainly in the liver, the main storage site for iron in the body. Results of recent studies have clearly shown that these pathologic events are induced by iron-generated reactive oxygen species and lipid peroxidation by-products. Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix components in the liver, is a dynamic process, from chronic liver damage to end-stage liver cirrhosis. Iron-induced oxidant stress is involved in this process (1) as the primary cause of parenchymal cell necrosis or (2) as activator of cells that are effectors [e.g., hepatic stellate cells, (myo)fibroblasts] or key mediators (e.g., Kupffer cells) of hepatic fibrogenesis (or through both mechanisms). Beyond their effect as direct cytotoxic agents, iron and free radicals may trigger increased synthesis of collagen in myofibroblast-like cells as well as activate granulocytes and Kupffer cells, resulting in an increased formation of cytokines and eicosanoids and further reactive oxygen species. This may constitute a cascade of amplifying loops, which perpetuate the fibrogenic process. The fibrogenic potential of iron is even more dramatic when iron acts in concert with other hepatotoxins such as alcohol. In this instance, even if tissue iron levels are only slightly elevated, the toxic effect of alcohol or its metabolites may be amplified and propagated with rapid acceleration of the liver disease. At the molecular level, the presence of catalytically active “free iron” may (1) contribute directly to the hepatotoxicity of alcohol or (2) enhance the generation of cytokine and fibrogenic mediators from resident Kupffer cells (or be involved in both ways). A challenge for future research is to develop therapeutic tools able to block “redox-active” free iron in the cell.

Introduction

Iron is a vital micronutrient, but its chemistry greatly limits its utilization and also sets the basis for its toxicity. The capacity of readily exchanging electrons in aerobic conditions makes iron essential for fundamental cell functions, such as DNA synthesis, transport of oxygen and electrons, and cell respiration. On the other hand, because human beings have no means to control iron excretion, excess iron, regardless of the route of entry, accumulates in parenchymal organs and threatens cell viability. In fact, a number of disease states, due to both a primary defect of iron metabolism (e.g., hemochromatosis) and acquired causes (e.g., iron-loading anemias, alcoholic and viral liver disease) (Fig. 1), are pathogenically linked to excess iron. In many of these conditions, iron-removal therapy is an effective lifesaving strategy. Untreated iron overload disease leads to organ fibrosis and cancer. It is now clear that iron toxicity, when acting on its own or in concert with other hepatotoxins (e.g., alcohol), is mediated by oxidative stress–driven damage and fibrogenesis (Pietrangelo, 1996).