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 beta1 (TGF-beta1). 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-beta1. 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-beta1 by HNE appears to be involved in the pathogenesis of these and similar diseases characterized by fibrosclerosis.

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A large spectrum of pro‐oxidant agents, including molecules with lipoperoxidative effect, can modulate gene expression through modification of the DNA binding activity of the transcription factors activator protein 1 (AP‐1) and nuclear factor kappa B (NF‐κB). In this study the effect on these redox‐sensitive factors by 4‐hydroxy‐2‐nonenal (HNE), a major aldehydic product of lipid peroxidation, was examined in two cell lines of the macrophage type. Incubation in the presence of μM concentrations of the aldehyde led to a rapid increase of AP‐1 binding with a transient maximum 30 min from HNE addition to the culture medium in both cell lines. On the contrary, HNE did not stimulate nuclear translocation of NF‐κB. The diverging effect of HNE on the two transcription factors is likely related to the demonstrated differential activation pathway of AP‐1 and NF‐κB in macrophages. The HNE‐induced activation of AP‐1 suggests the aldehyde's involvement in the regulatory mechanisms of cell proliferation and differentiation.

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