| A glutamine synthetase inhibitor increases survival and decreases cytokine response in a mouse model of acute liver failure. | |
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MedLine Citation:
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PMID: 21745296 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Background: Acute liver failure (ALF) can be induced in mice by administering Escherichia coli lipopolysaccharide (LPS) and D-galactosamine (D-GalN), which induce an inflammatory response involving tumour necrosis factor (TNF)-α production and a hepatocyte-specific transcriptional block. Under these conditions, binding of TNF-α to its cognate receptor on hepatocytes eventually leads to their apoptosis. Aims: As part of an effort to identify drugs to treat this disease model, we have investigated whether the glutamine synthetase inhibitor methionine sulfoximine (MSO) could play a protective role, given its effectiveness in the inhibition of brain swelling associated with hyperammonaemia. Methods: Mouse survival, glutamine synthetase activity, hepatocyte apoptosis and induction of inflammatory cytokines were measured in mice treated with MSO before an intraperitoneal injection of LPS/D-GalN. The effect of MSO on viability and on TNF-α release was also assessed on inflammatory and liver cells. Results: We have found that, in mice treated with LPS/D-GalN, MSO (i) drastically increases animal survival; (ii) sharply reduces glutamine synthetase activity, without inhibiting its other target, γ-glutamyl cysteine synthetase; (iii) inhibits death receptor-mediated apoptosis in hepatocytes upstream to cytokine binding; (iv) strongly reduces the overall inflammatory cytokine response, including a significant decrease in TNF-α induction in vivo and ex vivo, and in the interferon-γ level and signalling. Conclusions: These results demonstrate that the MSO target glutamine synthetase is required for the early steps of the cytokine response to endotoxins, and that its pharmacological inhibition may be exploited to treat inflammation. |
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Authors:
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Amruta A Jambekar; Elena Palma; Luca Nicolosi; Andrea Rasola; Valeria Petronilli; Federica Chiara; Paolo Bernardi; Richard Needleman; William S A Brusilow |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-31 |
Journal Detail:
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Title: Liver international : official journal of the International Association for the Study of the Liver Volume: - ISSN: 1478-3231 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-7-12 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101160857 Medline TA: Liver Int Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2011 John Wiley & Sons A/S. |
Affiliation:
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Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA Department of Biomedical Sciences, University of Padova, Padova, Italy Department of Environmental Medicine and Public Health, University of Padova, Padova, Italy. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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