Evidence that 5‐lipoxygenase and acetylated cyclooxygenase 2‐derived eicosanoids regulate leukocyte–endothelial adherence in response to aspirin

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Abstract
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 E2 (PGE2) to 15‐epi‐lipoxin A4 (15‐epi‐LXA4 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 B4 (LTB4) formation. 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). 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 ∼70% reversion of antiadhesive effect of aspirin. In contrast, inhibition of neutrophil's 5‐LOX pathway with 1 μM ZD2138, a selective 5‐LOX inhibitor, 1 μM BAY‐X‐1005, a FLAP inhibitor, or 100 μM licofelone, a dual COX/5‐LOX inhibitor, did not affect antiadhesive properties of aspirin. Exposure to celecoxib (100 μM) or rofecoxib (10 μM) 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. Treatment with LXA4 reduced PMN adhesion to HUVEC and counteracted the proadhesive effect of celecoxib. In contrast, exposure to Boc‐1, an LXA4 antagonist, counteracts the antiadhesive activities of aspirin. Exposure to U75302, an LTB4 receptor antagonist, enhances the antiadesive effect of aspirin. 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 LXA4, ZD2138 and U75302 inhibited these changes. 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 anti‐inflammatory drugs at the leukocyte–endothelial cell interface. British Journal of Pharmacology (2003) 139, 1351–1359. doi:10.1038/sj.bjp.0705356

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