期刊
MOLECULAR MEDICINE
卷 18, 期 7, 页码 1128-1135出版社
FEINSTEIN INST MED RES
DOI: 10.2119/molmed.2012.00088
关键词
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资金
- National Key Basic Research Program of China [2009CB522402]
- Science and Technology Commission of Shanghai Municipality (STCSM) [09JC1405600]
- the Division of Biomedicine, STCSM [10411951300]
- Shanghai Municipal Health Bureau (SMHB) [2011227]
- Foundation of Changzheng Hospital [200910]
Flurbiprofen acts as a nonselective inhibitor for cyclooxygenases (COX-1 and COX-2), but its impact on hepatic ischemia/reperfusion (I/R) injury remains unclear, Mice were randomized into sham, I/R and flurbiprofen (Flurb) groups. The hepatic artery and portal vein to the left and median liver lobes were occluded for 90 min and unclamped for reperfusion to establish a model of segmental (70%) warm hepatic ischemia. Pretreatment of animals with flurbiprofen prior to I/R insult significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and prevented hepatocytes from I/R-induced apoptosis/necrosis. Moreover, flurbiprofen dramatically inhibited mitochondrial permeability transition (MPT) pore opening, and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that flurbiprofen markedly inhibited glycogen synthase kinase (GSK)-3 beta activity and increased phosphorylation of GSK-3 beta at Ser9, which, consequently, could modulate the adenine nucleotide translocase (ANT)-cyclophilin D (CyP-D) complex and the susceptibility to MPT induction. Therefore, administration of flurbiprofen prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through inhibition of MPT and inactivation of GSK-3 beta, and provides experimental evidence for clinical use of flurbiprofen to protect liver function in surgical settings in addition to its conventional use for pain relief. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00088
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