{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T12:49:49Z","timestamp":1789735789007,"version":"4.0.1"},"reference-count":34,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2009,1,30]],"date-time":"2009-01-30T00:00:00Z","timestamp":1233273600000},"content-version":"vor","delay-in-days":2009,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2003,8]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Unlike other nonsteroidal anti\u2010inflammatory drugs that inhibit formation of cyclooxygenase (COX)\u2010dependent eicosanoids, acetylation of COX\u20102 by aspirin switches eicosanoid biosynthesis from prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>) to 15\u2010epi\u2010lipoxin A<jats:sub>4<\/jats:sub> (15\u2010epi\u2010LXA<jats:sub>4<\/jats:sub> or aspirin\u2010triggered lipoxin, ATL). ATL formation by activated leukocytes (PMN) requires the intervention of 5\u2010lipoxygenase (5\u2010LOX), an enzyme that is involved in leukotriene B<jats:sub>4<\/jats:sub> (LTB<jats:sub>4<\/jats:sub>) formation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In the present study, we have examined the role of acetylated COX\u20102 and 5\u2010LOX in modulating antiadhesive effects of aspirin on adhesion of PMN to endotoxin (LPS)\u2010primed human umbilical endothelial cells (HUVEC).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Treating PMN\/HUVEC cocultures with aspirin resulted in a concentration\u2010dependent inhibition of cell\u2010to\u2010cell adhesion induced by LPS. Treating HUVEC with selective COX\u20102 inhibitors, celecoxib and rofecoxib, caused an \u223c70% reversion of antiadhesive effect of aspirin. In contrast, inhibition of neutrophil's 5\u2010LOX pathway with 1 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc> ZD2138, a selective 5\u2010LOX inhibitor, 1 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc> BAY\u2010X\u20101005, a FLAP inhibitor, or 100 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc> licofelone, a dual COX\/5\u2010LOX inhibitor, did not affect antiadhesive properties of aspirin.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Exposure to celecoxib (100 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) or rofecoxib (10 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) completely suppressed ATL formation caused by aspirin without affecting LTB<jats:sub>4<\/jats:sub> levels. ZD2138, licofelone and BAY\u2010X\u20101005 inhibited ATL formation as well as LTB<jats:sub>4<\/jats:sub> generation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Treatment with LXA<jats:sub>4<\/jats:sub> reduced PMN adhesion to HUVEC and counteracted the proadhesive effect of celecoxib. In contrast, exposure to Boc\u20101, an LXA<jats:sub>4<\/jats:sub> antagonist, counteracts the antiadhesive activities of aspirin. Exposure to U75302, an LTB<jats:sub>4<\/jats:sub> receptor antagonist, enhances the antiadesive effect of aspirin.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Reversal of antiadhesive activities of aspirin by celecoxib was associated with increased expression of LFA\u20101 on PMN and E\u2010selectin on HUVEC. Addition of LXA<jats:sub>4<\/jats:sub>, ZD2138 and U75302 inhibited these changes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>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\u20101 inhibitors and suggests that the LTB<jats:sub>4<\/jats:sub>\/ATL balance modulates pro\u2010 and antiadhesive activity of nonsteroidal anti\u2010inflammatory drugs at the leukocyte\u2013endothelial cell interface.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2003) <jats:bold>139<\/jats:bold>, 1351\u20131359. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705356\">10.1038\/sj.bjp.0705356<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0705356","type":"journal-article","created":{"date-parts":[[2003,7,30]],"date-time":"2003-07-30T15:17:24Z","timestamp":1059578244000},"page":"1351-1359","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Evidence that 5\u2010lipoxygenase and acetylated cyclooxygenase 2\u2010derived eicosanoids regulate leukocyte\u2013endothelial adherence in response to aspirin"],"prefix":"10.1111","volume":"139","author":[{"given":"Stefano","family":"Fiorucci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Distrutti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Mencarelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Morelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan A","family":"Laufor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Cirino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L","family":"Wallace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,1,30]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"197","article-title":"Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, immunoglobulin\u2013cell adhesion molecules, and selectins","volume":"50","author":"ALPIN A.E.","year":"1998","journal-title":"Pharmacol. 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