Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 139, Issue 7, Pages 1351-1359Publisher
WILEY
DOI: 10.1038/sj.bjp.0705356
Keywords
leukotriene B4; lipoxin; aspirin-triggered lipoxin; neutrophils/endothelium adherence; aspirin; 5-lipoxigenase; cyclooxygenase; celcoxib; rofecoxib
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1 Unlike other nonsteroidal anti-inflammatory drugs that inhibit formation of cyclooxygenase (COX)-dependent eicosanoids, acetylation of COX-2 by aspirin switches eicosanoid biosynthesis from prostaglandin E-2 (PGE(2)) to 15-epi-lipoxin A(4) (15-epi-LXA(4) or aspirin-triggered lipoxin, ATL). ATL formation by activated leukocytes (PMN) requires the intervention of 5-lipoxygenase (5-LOX), an enzyme that is involved in leukotriene B-4 (LTB4) formation. 2 In the present study, we have examined the role of acetylated COX-2 and 5-LOX in modulating antiadhesive effects of aspirin on adhesion of PMN to endotoxin (LPS)-primed human umbilical endothelial cells ( HUVEC). 3 Treating PMN/HUVEC cocultures with aspirin resulted in a concentration-dependent inhibition of cell-to-cell adhesion induced by LPS. Treating HUVEC with selective COX-2 inhibitors, celecoxib and rofecoxib, caused an approximate to70% reversion of antiadhesive effect of aspirin. In contrast, inhibition of neutrophil's 5-LOX pathway with 1 muM ZD2138, a selective 5-LOX inhibitor, 1 muM BAY-X-1005, a FLAP inhibitor, or 100 muM licofelone, a dual COX/5-LOX inhibitor, did not affect antiadhesive properties of aspirin. 4 Exposure to celecoxib (100 muM) or rofecoxib (10 muM) completely suppressed ATL formation caused by aspirin without affecting LTB4 levels. ZD2138, licofelone and BAY-X-1005 inhibited ATL formation as well as LTB4 generation. 5 Treatment with LXA(4) reduced PMN adhesion to HUVEC and counteracted the proadhesive effect of celecoxib. In contrast, exposure to Boc-1, an LXA(4) antagonist, counteracts the antiadhesive activities of aspirin. Exposure to U75302, an LTB4 receptor antagonist, enhances the antiadesive effect of aspirin. 6 Reversal of antiadhesive activities of aspirin by celecoxib was associated with increased expression of LFA-1 on PMN and E-selectin on HUVEC. Addition of LXA(4), ZD2138 and U75302 inhibited these changes. 7 The present results support the notion that inhibition of ATL formation is mechanistically linked to the reversal of the antiadhesive activity of aspirin caused by selective COX-1 inhibitors and suggests that the LTB4/ATL balance modulates pro- and antiadhesive activity of nonsteroidal antiinflammatory drugs at the leukocyte-endothelial cell interface.
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