Oxidative and nitrosative stress and fibrogenic response - PubMed (original) (raw)

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Oxidative and nitrosative stress and fibrogenic response

R Urtasun et al. Clin Liver Dis. 2008 Nov.

Abstract

Uncontrolled production of collagen I is the main feature of liver fibrosis. Following a fibrogenic stimulus such as alcohol, hepatic stellate cells (HSC) transform into an activated collagen-producing cell. In alcoholic liver disease, numerous changes in gene expression are associated with HSC activation, including the induction of several intracellular signaling cascades, which help maintain the activated phenotype and control the fibrogenic and proliferative state of the cell. Detailed analyses for understanding the molecular basis of the collagen I gene regulation have revealed a complex process involving reactive oxygen species (ROS) as key mediators. Less is known, however, about the contribution of reactive nitrogen species (RNS). In addition, a series of cytokines, growth factors, and chemokines, which activate extracellular matrix (ECM)-producing cells through paracrine and autocrine loops, contribute to the fibrogenic response.

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Figures

Fig. 1

Generation of NO· by NOS in liver cells. NO· is relatively unstable in the presence of O2 and will rapidly and spontaneoulsy auto-oxidize to yield a variety of nitrogen oxides.NO· also reacts with O2· − to generate ONOO−. Although ONOO− is relatively stable, it has a pKa of 6.8, which implies that substantial amounts of ONOO− will be protonated at physiologic pH to yield peroxynitrous acid. This conjugate acid rapidly decomposes to yield NO3−. Nitration of tyrosine residues by ONOO− forms the stable product, 3-nitrotyrosine (3-NT, the footprint for ONOO−) by addition of a nitro group to the 3-position adjacent to the hydroxyl group of tyrosine.

Fig. 2

In liver injury, ROS and RNS are generated in all liver cells. O2· − can react with NO· to generate ONOO− and other metabolites that may impact the HSC fibrogenic response in the early stages of cellular activation. ONOO− and its metabolites lower collagen I protein by increasing TNFα and inducing nitration of MMP1 with the subsequent cleavage of collagen I. These effects can be reverted by ONOO− chelating agents.

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Oxidative and nitrosative stress and fibrogenic response - PubMed (original) (raw)