{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:59:02Z","timestamp":1787162342554,"version":"build-2736575974"},"reference-count":62,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2011,5,31]],"date-time":"2011-05-31T00:00:00Z","timestamp":1306800000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2011,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    Acute liver failure (ALF) can be induced in mice by administering\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    lipopolysaccharide (LPS) and D\u2010galactosamine (D\u2010GalN), which induce an inflammatory response involving tumour necrosis factor (TNF)\u2010\u03b1 production and a hepatocyte\u2010specific transcriptional block. Under these conditions, binding of TNF\u2010\u03b1 to its cognate receptor on hepatocytes eventually leads to their apoptosis.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Aims:<\/jats:bold>\n                    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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    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\u2010GalN. The effect of MSO on viability and on TNF\u2010\u03b1 release was also assessed on inflammatory and liver cells.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    We have found that, in mice treated with LPS\/D\u2010GalN, MSO (i) drastically increases animal survival; (ii) sharply reduces glutamine synthetase activity, without inhibiting its other target, \u03b3\u2010glutamyl cysteine synthetase; (iii) inhibits death receptor\u2010mediated apoptosis in hepatocytes upstream to cytokine binding; (iv) strongly reduces the overall inflammatory cytokine response, including a significant decrease in TNF\u2010\u03b1 induction\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>ex vivo<\/jats:italic>\n                    , and in the interferon\u2010\u03b3 level and signalling.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusions:<\/jats:bold>\n                    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.\n                  <\/jats:p>","DOI":"10.1111\/j.1478-3231.2011.02553.x","type":"journal-article","created":{"date-parts":[[2011,5,31]],"date-time":"2011-05-31T22:17:06Z","timestamp":1306880226000},"page":"1209-1221","source":"Crossref","is-referenced-by-count":21,"title":["A glutamine synthetase inhibitor increases survival and decreases cytokine response in a mouse model of acute liver failure"],"prefix":"10.1111","volume":"31","author":[{"given":"Amruta A.","family":"Jambekar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Palma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Nicolosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Rasola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Petronilli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Chiara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Bernardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Needleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William S. 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