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 ¹

Abstract

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.

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

“…The physiological concentration of HNE in the plasma is reportedly from 0.3-0.7 μM (164,165) but its concentration can reach as high 10 μM or more in plasma membrane under conditions of oxidative stress (166,167). While HNE is therefore considered as a biomarker of oxidative stress (167,168), it is also implicated in various oxidative stress-related diseases, including atherosclerosis (169), neurodegenerative diseases (170), and fibrosis (171).…”

TGFβ1 expression in colonic mucosa: modulation by dietary lipids

“…HNE can control growth and differentiation, cell cycle progression and apoptosis. Indeed, this molecule may be considered as antiproliferative, being able to regulate genes encoding for other molecules such as c-myc, c-myb, cyclins, p21 and TGF-b1 [7,50,54,88,110].…”

“…Such HNE/MDA-protein adducts appear to be reliable markers of oxidative reactions [10,19,86,87,118]. Pathophysiological amounts of HNE induce TGFb1 expression and synthesis in promonocytic and macrophagic cells [54] and augment both expression and synthesis of procollagen type I in primary cultures of human stellate cells [81]. The signaling pathways adopted by this aldehyde in modulating these genes, and its related hydroxyalkenal compounds, most likely imply the activation of kinases involved in the regulation of the redox-sensitive transcription factor AP-1 [55].…”

“…Because of the demonstrated marked ability of HNE to up-regulate expression and synthesis of TGFb1 [54], and its role as a negative growth controller, the combined low content of HNE and TGFb1 found in colon cancer tissue, could provide a favorable condition for tumor survival. In fact, transformed cells could be safeguarded from the antiproliferative control exerted by these molecules.…”

“…Certain lipid oxidation products may enhance the activity of several inflammatory cytokines, including transforming growth factor b1 (TGFb1), and thus these products may exert pro-inflammatory and pro-fibrogenic effects within the colon mucosa [54,86]. TGFb1 is normally expressed in endothelial, hematopoietic and mesenchymal cells, and it is well known to be a regulator of proliferation, survival, differentiation and apoptosis in different cell types.…”