Publication: Oxidative stress, isoprostanes and hepatic fibrosis
Authors
Comporti, Mario ; Arezzini, Beatrice ; Signorini, Cinzia ; Vecchio, Daniela ; Gardi, Concetta
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
An introduction to oxidative stress
enlightening the spreading of interest in lipid
peroxidation in the 60's and in the identification of
cytotoxic aldehydes originating from it is given. The
discovery of F2
-isoprostanes as specific markers of
oxidative stress is described. Isoprostanes are also
agonists of important biological effects. Since a
relationship between oxidative stress and collagen
hyperproduction has been previously suggested, and
since lipid peroxidation products (aldehydes) have been
proposed as possible mediators of liver fibrosis, we
investigated whether collagen synthesis is induced by
F2
-isoprostanes, which can posses receptors for signal
transduction pathways. In a rat model of carbon
tetrachloride-induced hepatic fibrosis, plasma
isoprostanes were markedly elevated for the entire
experimental period and hepatic collagen content was
also increased. Moreover, when hepatic stellate cells
(HSC) isolated from normal livers were cultured up to
activation and then treated with F2
-isoprostanes (8-epiPGF2α
) in the concentration range found in the in vivo
studies (10-9 to 10-8 M), a striking increase in DNA
synthesis, in cell proliferation and in collagen synthesis
was observed. F2
-isoprostanes also increased the
production of transforming growth factor-ß1 by U937
cells, assumed as a model of Kupffer cells or liver
macrophages. The hypothesis that F2
-isoprostanes
generated by lipid peroxidation in hepatocytes mediate
HSC proliferation and collagen hyperproduction, seen in
this experimental hepatic fibrosis, was reinforced by the
demonstration, by using immunoblot analysis, that
isoprostane receptors identical or analogous to those for
thromboxane A2
(TxA2
r) are present in HSC.
Immunocytochemical studies showed the major
localization of TxA2
r in the perinuclear site and its
colocalization with α-smooth muscle actin.
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