Relative contribution of acetylated cyclo-oxygenase (COX)-2 and 5-lipooxygenase (LOX) in regulating gastric mucosal integrity and adaptation to aspirin.
In addition to inhibiting formation of prothrombotic eicosanoids, aspirin causes the acetylation of cyclooxygenase (COX)-2. The acetylated COX-2 remains active, and upon cell activation, initiates the generation of 15R-HETE, a lipid substrate for 5-lipoxygenase (LOX) leading to the formation of 15-epi-LXA4 (also termed "aspirin-triggered lipoxin," or ATL). Because ATL potently inhibits polymorphonuclear cell (PMN) function, we assessed the relative contribution of this lipid mediator in conjunction with another 5-LOX product, the leukotriene (LT)B4, to the pathogenesis of acute damage and gastric adaptation to aspirin. Data presented herein indicate that acute injury and gastric adaptation to aspirin is associated with ATL generation. Administration of COX inhibitors (celecoxib, indomethacin, ketoprofen) to aspirin-treated rats exacerbated acute injury and abolished adaptation to aspirin. Moreover, it inhibited ATL formation and caused a four- to fivefold increase in LTB4 synthesis. In contrast, licofelone, a COX/5-LOX inhibitor, did not exacerbate acute gastric injury nor did it interfere with gastric adaptation to aspirin. Although licofelone blocked ATL and LTB4 formation in aspirin-treated rats, it attenuated aspirin-induced gastric PMN margination. These findings indicate that the balance between the production of LTB4 and ATL modulates PMN recruitment/function and gastric mucosal responses to aspirin.
Fiorucci
Stefano
S
Clinica di Gastroenterologia ed Epatologia, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Perugia, Italy. fiorucci@unipg.it
Distrutti
Eleonora
E
de Lima
Octavio Menezes
OM
Romano
Mario
M
Mencarelli
Andrea
A
Barbanti
Miriam
M
Palazzini
Ernesto
E
Morelli
Antonio
A
Wallace
John L
JL
D000085:Acetates / Q000633:toxicity; D000107:Acetylation; D000222:Adaptation, Physiological; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000502:physiology*; D001241:Aspirin / Q000633:toxicity*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007527:Isoenzymes / Q000737:chemistry / Q000502:physiology*; D007975:Leukotriene B4 / Q000096:biosynthesis; D044045:Lipoxins; D016859:Lipoxygenase Inhibitors / Q000633:toxicity; D008954:Models, Biological; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000502:physiology*; D011758:Pyrroles / Q000633:toxicity; D051381:Rats
D000085:Acetates; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D007527:Isoenzymes; D044045:Lipoxins; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles; C040527:lipoxin A4; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C088092:licofelone; D001241:Aspirin