Ibuprofen administration attenuates serum TNF-alpha levels, hepatic glutathione depletion, hepatic apoptosis and mouse mortality after Fas stimulation.
Fas stimulation recruits neutrophils and activates macrophages that secrete tumor necrosis factor-alpha (TNF-alpha), which aggravates Fas-mediated liver injury. To determine whether nonsteroidal anti-inflammatory drugs modify these processes, we challenged 24-hour-fasted mice with the agonistic Jo2 anti-Fas antibody (4 microg/mouse), and treated the animals 1 h later with saline or ibuprofen (250 mg/kg), a dual cyclooxygenase (COX)-1 and COX-2 inhibitor. Ibuprofen attenuated the Jo2-mediated recruitment/activation of myeloperoxidase-secreting neutrophils/macrophages in the liver, and attenuated the surge in serum TNF-alpha. Ibuprofen also minimized hepatic glutathione depletion, Bid truncation, caspase activation, outer mitochondrial membrane rupture, hepatocyte apoptosis and the increase in serum alanine aminotransferase (ALT) activity 5 h after Jo2 administration, to finally decrease mouse mortality at later times. The concomitant administration of pentoxifylline (decreasing TNF-alpha secretion) and infliximab (trapping TNF-alpha) likewise attenuated the Jo2-mediated increase in TNF-alpha, the decrease in hepatic glutathione, and the increase in serum ALT activity 5 h after Jo2 administration. The concomitant administration of the COX-1 inhibitor, SC-560 (10 mg/kg) and the COX-2 inhibitor, celecoxib (40 mg/kg) 1 h after Jo2 administration, also decreased liver injury 5 h after Jo2 administration. In contrast, SC-560 (10 mg/kg) or celecoxib (40 or 160 mg/kg) given alone had no significant protective effects. In conclusion, secondary TNF-alpha secretion plays an important role in Jo2-mediated glutathione depletion and liver injury. The combined inhibition of COX-1 and COX-2 by ibuprofen attenuates TNF-alpha secretion, glutathione depletion, mitochondrial alterations, hepatic apoptosis and mortality in Jo2-treated fasted mice.
Institut National de la Santé et de la Recherche Médicale (INSERM), U773, Centre de Recherche Biomédicale Bichat Beaujon (CRB3), Equipe Mitochondries et Foie, BP 416, F-75018, Paris, France.
Sophie
S
Cazanave
Nathalie
N
Vadrot
Marina
M
Tinel
Alain
A
Berson
Philippe
P
Lettéron
Isabelle
I
Larosche
Véronique
V
Descatoire
Gérard
G
Feldmann
Marie-Anne
MA
Robin
Dominique
D
Pessayre
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D005978:Glutathione / Q000172:deficiency*; D006505:Hepatitis / Q000201:enzymology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D007052:Ibuprofen / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood* / Q000378:metabolism; D019014:fas Receptor / Q000633:toxicity*
D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D005978:Glutathione; D007052:Ibuprofen