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Relative contribution of acetylated cyclooxygenase (COX)‐2 and 5‐lipooxygenase (LOX) in regulating gastric mucosal integrity and adaptation to aspirin
Author(s) -
Fiorucci Stefano,
Distrutti Eleonora,
De Lima Octavio Menezes,
Romano Mario,
Mencarelli Andrea,
Barbanti Miriam,
Palazzini Ernesto,
Morelli Antonio,
Wallace John L.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0777fje
Subject(s) - aspirin , cyclooxygenase , pharmacology , medicine , chemistry , celecoxib , biochemistry , enzyme
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 15 R ‐HETE, a lipid substrate for 5‐lipoxygenase (LOX) leading to the formation of 15‐epi‐LXA 4 (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)B 4 , 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 LTB 4 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 LTB 4 formation in aspirin‐treated rats, it attenuated aspirin‐induced gastric PMN margination. These findings indicate that the balance between the production of LTB 4 and ATL modulates PMN recruitment/function and gastric mucosal responses to aspirin.