Reactive nitrogen species switch on early extracellular matrix remodeling via induction of MMP1 and TNFalpha
Raquel Urtasun1, Francisco Javier Cubero, María Vera
1Department of Medicine, Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York 10029, USA.
Gastroenterology
|March 3, 2009
Summary
Peroxynitrite (ONOO-) can reduce liver injury by decreasing collagen production and HSC activation in early stages. However, this protective effect is diminished in advanced liver disease due to higher glutathione levels.
Area of Science:
- Hepatology
- Biochemistry
- Cell Biology
Background:
- Liver injury generates reactive oxygen and nitrogen species, leading to peroxynitrite (ONOO-) formation.
- Extracellular matrix remodeling is a key process in liver fibrosis.
Purpose of the Study:
- To investigate the role of peroxynitrite (ONOO-) and its metabolites in modulating extracellular matrix remodeling in liver injury.
- To determine if ONOO- influences hepatic stellate cell (HSC) activation and fibrogenesis.
Main Methods:
- Incubation of hepatic stellate cells (HSC) with ONOO- or SIN-1 (a ONOO- donor).
- Analysis of collagen gene expression (COL1A1, COL1A2), protein levels, and enzyme activity (MMP1, MMP13, TNFalpha).
- In vivo studies using rat models of alcohol-induced liver injury and CCl4-induced liver injury.
Main Results:
- ONOO- down-regulated collagen I and alpha-Sma proteins while up-regulating MMP1 and TNFalpha, indicating decreased HSC activation.
- ONOO- increased nitrosylation of MMP1/MMP13 and transactivation of MMP1, MMP13, and TNFalpha promoters.
- In vivo, ONOO- showed a protective role in the early fibrogenic response, but this was reduced in highly activated HSC due to higher glutathione levels and TGFbeta production.
Conclusions:
- Peroxynitrite (ONOO-) can activate a protective mechanism in hepatic stellate cells (HSC) during the early stages of liver injury.
- The anti-fibrogenic effects of ONOO- are limited in advanced liver disease where HSC are highly activated.
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