Antonella Scavazza

The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor beta1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis.

An increasing number of reports underscore the frequent association of fibrosclerotic diseases of lung, liver, arterial wall, brain, etc., with the accumulation of oxidatively modified lipids and proteins. A cause‐and‐effect relationship has been proposed between cellular oxidative damage and increased fibrogenesis based on the fact that experimental treatment with antioxidants either prevents or quenches the fibrotic process. With some peculiarities in the different organs, fibrosclerosis is essentially the result of the interaction of macrophages and extracellular matrix‐producing cells. The cross‐talk is mediated by fibrogenic cytokines, among which the most important appears to be transforming growth factor β1 (TGF‐β1). This report describes treatment of different types of macrophage, of both human and murine origin, with 4‐hydroxy‐2,3‐nonenal (HNE) a major aldehyde end product of membrane lipid oxidation found consistently to induce both mRNA expression and synthesis of TGF‐β1. Since increased HNE levels have been demostrated in the cirrhotic liver and in the oxidatively modified low‐density human lipoproteins associated with atherosclerosis, the up‐regulation of macrophage TGF‐β1 by HNE appears to be involved in the pathogenesis of these and similar diseases characterized by fibrosclerosis.—Leonarduzzi, G., Scavazza, A., Biasi, F., Ghiarpotto, E., Camandola, S., Vogl, S., Dargel, R., Poli, G. The lipid peroxidation end product 4‐hydroxy‐2,3‐nonenal up‐regulates transforming growth factor β1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis. FASEB J. 11, 851–857 (1997)

Oxidative damage and transforming growth factor beta 1 expression in pretumoral and tumoral lesions of human intestine.

The aim of this study was to evaluate a possible relationship between oxidative stress and transforming growth factor beta 1 (TGF beta 1) expression in human colon adenocarcinoma. Crohns disease, an inflammatory pathology of the intestine often regarded to as precancerous, was also examined. Indices of impaired redox balance were monitored in blood and in bioptic samples from 10 adult patients with adenocarcinoma of the colon and from five patients with Crohns disease. On tissue samples TGF beta 1 mRNA expression was also determined. Ten healthy adults provided normal reference values for plasma indices of oxidative stress, and normal tissue distant from the lesions was used for comparative analysis. Fluorescent adducts with plasma proteins of malonaldehyde (MDA) and 4-hydroxynonenal (HNE) were significantly lower than controls in the plasma from cancer patients and significantly higher in the plasma from Crohns patients. In adenocarcinoma biopsies, susceptibility to lipid peroxidation processes and TGF beta 1 expression were below the relative control; in Crohns disease, lipid peroxidation and cytokine expression were both above the relative control. The findings obtained suggest the existence of an association between oxidative damage and fibrogenic cytokine expression in the human intestine. Further studies are needed to conclusively prove the correlation between the two events.

Oxidative stress in the development of human ischemic hepatitis during circulatory shock

An increasing number of studies support the involvement of free radical-mediated oxidative reactions in the pathogenesis of tissue injury following ischemia reperfusion. In particular, a condition of oxidative stress is evident in patients with circulatory shock, a disease process often complicated by progressive organ failure sustained by inflammatory reactions. In all shock patients without signs of organ failure, a consistent increase of intermediate and final products of lipid peroxidation (lipid peroxides and aldehydes respectively) was observed. Impairment of the redox equilibrium in the tissues of these patients was confirmed by a significant reduction of glutathione and vitamin E hematic concentrations. Moreover, a selective increase of plasma aldehyde-protein adducts, actual proof of oxidative damage of macromolecules, is only present in the shock patients who, in addition, show hepatic cytolysis (ischemic hepatitis) as estimated by plasma levels of LDH5 isoenzyme. Aldehyde adducts well mark the progression of the disease towards multiple organ failure. Finally, the good statistical correlation between aldehyde-modified proteins and LDH5, as well as their distinct behaviour in control and ischemic hepatitis, support the involvement of oxidative damage in the expression and worsening of circulatory shock.

In vivo potentiation of 1,2-dibromoethane hepatotoxicity by ethanol through inactivation of glutathione-s-transferase.

In the rat, a single ethanol (EtOH) pretreatment (2.5 g/kg b.w., per os) was able to strongly enhance the cytotoxicity of 1,2-dibromoethane (DBE)(87 mg/kg b.w., per os). The principal metabolic routes of DBE involve both oxidative and conjugative transformations. Microsomal cytochrome P450 content and dimethyl nitrosamine demethylase activity were not changed, while a significant loss of cytosolic total GSH-transferase was observed in rats killed 6 h after EtOH pretreatment. Pretreatment with methylpyrazole, an inhibitor of alcohol-dehydrogenase prevented the effects provoked by ethanol. The major EtOH metabolite, acetaldehyde. seemed thus to play a fundamental role in the mechanism responsible for the potentiation of DBE toxicity mediated by EtOH. To further support this hypothesis, disulfiram (75 mg/kg b.w.), an inhibitor of aldehyde dehydrogenase, was given i.p. to rats. When DBE was administered to disulfiram- and EtOH-pretreated rats, a marked increase of liver cytolysis was shown and cytosolic GSH-transferase activity was further inhibited if compared to that induced by EtOH treatment alone. The results are consistent with the hypothesis that EtOH given to rats increases DBE liver toxicity because its major metabolite, acetaldehyde, reduces the DBE conjugates to GSH transferase, with consequent shift of DBE metabolism to the oxidative route and accumulation of reactive oxidative intermediates no longer effectively conjugated with GSH.

OXIDATIVE DAMAGE AND FIBROSCLEROSIS IN VARIOUS TISSUES

A number of chronic disease processes affecting liver, lung, arteries, kidney and nervous system are characterized by excess deposition of collagen and other extracellular matrix proteins. Such degenerative condition is termed fibrosclerosis and has assumed much importance in human physiopathology.

Rat hepatocytes in single cell suspension: A still suitable system for lipid peroxidation studies

The investigation of toxic compounds which need a previous metabolic activation often gets advantage by the employment of cell suspensions, in most of the cases rat hepatocytes. In particular, this model system allows the characterization of lipid peroxidation kinetics, the evaluation of its pathogenetic role in the induction of cell death and the analysis of the interaction among different prooxidant compounds in bringing about both oxidative damage and cytolysis.