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Role of 4‐hydroxy‐2,3‐nonenal in the pathogenesis of fibrosis
Author(s) -
Chiarpotto Elena,
Castello Laura,
Leonarduzzi Gabriella,
Biasi Fiorella,
Poli Giuseppe
Publication year - 2005
Publication title -
biofactors
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.204
H-Index - 94
eISSN - 1872-8081
pISSN - 0951-6433
DOI - 10.1002/biof.5520240127
Subject(s) - fibrosis , chemistry , lipid peroxidation , inflammation , activator (genetics) , transforming growth factor , microbiology and biotechnology , pathogenesis , oxidative stress , cancer research , biochemistry , immunology , biology , medicine , gene
Transient activation of fibroblasts or fibroblast‐like cells to proliferate and to produce elevated quantities of extracellular matrix is essential to fibrosis. This activation is regulated by several cytokines produced by various inflammation‐associated cells. Among these, transforming growth factor beta1 (TGFβ1) is considered of major importance. Many studies have shown that lipid peroxidation play a key role in the initiation and progression of fibrosis in different organs. In fact, 4‐hydroxy‐2,3‐nonenal (HNE), the major aldehydic product of lipid peroxidation, is able to induce TGFβ1 expression and synthesis, and activation of activator protein‐1 (AP‐1) transcription factor. In this study, using the murine macrophage line J774‐A1, we show that these effects are strictly related to the chemical structure of HNE, since neither 2‐nonenal nor nonanal are biologically active to the same extent. Moreover, we demonstrate that HNE can indeed contribute to the onset of fibrosis by stimulating AP‐1 binding to DNA and consequently inducing TGFβ1 expression, since thiol‐group reagents, such as N‐ethylmaleimide and 4‐(chloro‐mercuri)‐benzenesulfonic acid, that down‐modulate HNE entrance and localisation inside the cell, prevent both phenomena. The possibility to control fibrogenic cytokine levels by means of antioxidant or dietetic treatments opens new potential pharmacological and nutritional horizons in the treatment of many chronic diseases characterised by excessive fibrosis.