Flurbiprofen, a cyclooxygenase inhibitor, protects mice from hepatic ischemia/reperfusion injury by inhibiting GSK-3β signaling and mitochondrial permeability transition.
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)-3β activity and increased phosphorylation of GSK-3β 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-3β, 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.
Departments of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Hailong
H
Fu
Huan
H
Chen
Chengcai
C
Wang
Haitao
H
Xu
Fang
F
Liu
Meng
M
Guo
Quanxing
Q
Wang
Xueyin
X
Shi
D000818:Animals; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005480:Flurbiprofen / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
D016861:Cyclooxygenase Inhibitors; D000081406:Peptidyl-Prolyl Isomerase F; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D005480:Flurbiprofen; D045304:Cytochromes c; D000226:Mitochondrial ADP, ATP Translocases; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D053453:Caspase 9; D021983:Cyclophilins; D002118:Calcium