Inhibition of 5-lipoxygenase-activating protein abrogates experimental liver injury: role of Kupffer cells.
Activation of Kupffer cells is a prominent feature of necro-inflammatory liver injury. We have recently demonstrated that 5-lipoxygenase (5-LO) and its accessory protein, 5-LO-activating protein (FLAP), are essential for the survival of Kupffer cells in culture, as their inhibition drives these liver resident macrophages to programmed cell death. In the current study, we explored whether the potent FLAP inhibitor, Bay-X-1005, reduces the number of Kupffer cells in vivo and whether this pharmacological intervention protects the liver from carbon tetrachloride (CCl(4))-induced damage. Rats treated with CCl(4) showed an increased number of Kupffer cells, an effect that was abrogated by the administration of Bay-X-1005 (100 mg/Kg body weight, per oral, daily). Consistent with a role for Kupffer cells in necro-inflammatory liver injury, partial depletion of Kupffer cells following FLAP inhibition was associated with a remarkable hepatoprotective action. Indeed, Bay-X-1005 significantly reduced the intense hepatocyte degeneration and large bridging necrosis induced by CCl(4) treatment. Moreover, Bay-X-1005 induced a reduction in the gelatinolytic activity of matrix metalloproteinase-2 (MMP-2) and a decrease in mRNA expression of tissue inhibitor of MMP-2. The FLAP inhibitor reduced leukotriene (LT)B(4) and cysteinyl LT levels and down-regulated 5-LO and FLAP protein expression in the liver. It is interesting that a significant increase in the hepatic formation of lipoxin A(4), an endogenous, anti-inflammatory lipid mediator involved in the resolution of inflammation, was observed after the administration of Bay-X-1005. These findings support the concept that modulation of the 5-LO pathway by FLAP inhibition may be useful in the prevention of hepatotoxin-induced necro-inflammatory injury.
Titos
Esther
E
Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona School of Medicine, Barcelona 08036, Spain.
Clària
Joan
J
Planagumà
Anna
A
López-Parra
Marta
M
González-Périz
Ana
A
Gaya
Joan
J
Miquel
Rosa
R
Arroyo
Vicente
V
Rodés
Joan
J
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002452:Cell Count; D056486:Chemical and Drug Induced Liver Injury; D002908:Chronic Disease; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology*; D015289:Leukotrienes / Q000378:metabolism; D044045:Lipoxins / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000187:drug effects / Q000235:genetics
D058927:5-Lipoxygenase-Activating Proteins; D002352:Carrier Proteins; D015289:Leukotrienes; D044045:Lipoxins; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011804:Quinolines; D012333:RNA, Messenger; C040527:lipoxin A4; D019716:Tissue Inhibitor of Metalloproteinase-2; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D002251:Carbon Tetrachloride; D001094:Arachidonate 5-Lipoxygenase; D020778:Matrix Metalloproteinase 2