Affiliations: Department of Clinical and Biological Sciences,
University of Torino, Regione Gonzole 10, 10043 Orbassano (TO), Italy | Department of Clinical and Biological Sciences,
Italian National Research Council, University of Torino, Regione Gonzole 10,
10043 Orbassano (TO), Italy
Note: [] Address for correspondence: Elena Chiarpotto, Department of
Clinical and Biological Sciences, University of Torino, Regione Gonzole 10,
10043 Orbassano (TO), Italy. Tel.: +39 0116705423; Fax: +39 0116705424; E-mail:
[email protected]
Abstract: 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.
