from their site of origin to attack distant targets and form Lipid peroxidation is an autocatalytic mechanism leading to covalent links with various molecules (adducts). 2 Different oxidative destruction of cellular membranes. The deleterious cytotoxic effects of MDA and HNE adduct formation have consequences of this mechanism are related in part to the been reported in vitro, including enzyme inactivation and formation of reactive aldehydic products that bind to intrainhibition of DNA, RNA, and protein synthesis. Therefore, or extracellular molecules to form adducts. Specific antibodies lipid peroxidation may cause severe damage, and it has been directed against malondialdehyde (MDA) and 4-hydroxynoassumed that this mechanism plays a key role in the pathonenal (HNE) adducts, major aldehydic metabolites of lipid genesis of several human diseases. Furthermore, recognition peroxidation, allowed us to investigate in situ, with an immuof lipid peroxidation involvement in the pathogenesis of a nohistochemical procedure, the occurrence of lipid peroxidadisease is of importance because the deleterious effects of this tion in a panel of different chronic liver diseases. Intracellular process might be prevented by administration of scavenging HNE and MDA adducts were detected respectively in 24 of systems or antioxidants. 4,5
39 cases (62%) and in 12 of 34 cases investigated (35%).
There is strong evidence that in humans, lipid peroxidation They were localized mainly in the cytoplasm of hepatocytes, is implicated in various diseases, including atherosclerosis, with the strongest staining observed in hemochromatosis, toxic injuries, and promotion of cancer. [7] Several studies Wilson's disease, and in areas of acute alcoholic hepatitis in also suggest that this mechanism is involved in some chronic cases of alcoholic liver diseases. A peculiar pattern of immuhuman liver diseases. 7,[10][11] In this context, it has been pronostaining was observed in primary biliary cirrhosis where posed, based on experimental investigations, that lipid peroxbiliary cells of destroyed but also intact bile ducts strongly idation may be a link between tissue injury and liver fibrosis expressed HNE adducts. The liver extracellular matrix also by modulating collagen gene expression. 12-15 displayed MDA adducts (30 of 34 cases, 88%) and HNE ad-Most previous studies investigating lipid peroxidation dealt ducts (23 of 39 cases, 59%). While HNE adducts were specifiwith blood and tissue extracts and used indirect quantitative cally localized on large bundles of collagen fibers, MDA admethods. Among them, the thiobarbituric acid test has been ducts were detected in a thin reticular network and in the most commonly applied assay. 16 Raising specific antibodsinusoidal cells around portal tracts or fibrous septa. In conies against MDA or HNE adducts enables a more direct and clusion, lipid peroxidation by-products are detectable in specific approach to evaluate the presence of these lipid perchronic liver diseases. Immunohistochemical results suggest oxidation-derived products. 17,18 that this mechanism is implicated very early in the pathogene-Because HNE and MDA are considered as the most reliable sis of some of these diseases. (HEPATOLOGY 1997;26:135-142.) indexes of free-radical stimulated lipid peroxidation, we evaluated here the occurrence of lipid peroxidation in different Lipid peroxidation is an autocatalytic mechanism leading chronic liver diseases by detecting the presence of MDA and to oxidative destruction of cellular membranes. 1 Their de-HNE adducts in liver tissue using an immunohistochemical struction can lead, per se, to cell death and also to the producprocedure. This enabled us to elucidate the cellular localization of toxic and reactive aldehydic metabolites. Among tion of these aldehydic products according to the cause of these, malondialdehyde (MDA) and 4-hydroxynonenal the liver diseases and their pathological features. (HNE) are the most important. These highly cytotoxic metabolites, produced in relatively large amounts, can diffuse
MATERIALS AND METHODS
Materials.
A total of 46 fixed, paraffin-embedded liver samples were retrospectively selected for the study. Hematein-eosin-safran and Masson's trichrome were performed for histological diagnosis.