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Despite nearly 100 years of wide usage, complete knowledge of the therapeutic impact of aspirin is still evolving1-3and new beneficial effects are being uncovered in cardiovascular disease and cancer.4 5 The irreversible acetylation of cyclo-oxygenase (COX)-1 and its more recently discovered isoform COX-21 6 with inhibition of prostaglandins is well appreciated and explains some, but not all, of the pharmacological actions of aspirin.
Another series of bioactive lipid mediators on which aspirin has an impact are lipoxins (LX), and their C15 epimers (15R), denoted aspirin triggered lipoxins (ATL, fig 1), which are biosynthesised by separate routes involving transcellular circuits.7 Native LX in the nanomolar range inhibit the adhesion and transmigration of polymorphonuclear leucocytes (PMNs)8-10 and hence serve as counter-regulatory signals operative in the resolution of inflammatory sites.11 12 Not only do LX serve counter-regulatory roles, but specific enantiomerically modified LX (ATL) may also be actual effectors of well established anti-inflammatory therapeutic actions of aspirin. The impact of 5S,6R,15S-trihydroxy-7,9,13- trans-11-cis-eicosatetraenoic acid (LXA4) and ATL was investigated in tumour necrosis factor (TNFα) initiated PMN responses in vitro and in vivo using the metabolically more stable LX analogues 15R/S-methyl-LXA4and 15-epi-16-(parafluoro)-phenoxy-LXA4. These compounds represent subtle modifications to the native LXA4 and ATL structure that prevent rapid metabolic inactivation of the lipoxin and 15-epi-LX structures.13 14 These compounds are also potent novel inhibitors of TNFα driven PMN associated inflammatory events in vitro as well as in vivo, as shown in a murine model with end points relevant to pulmonary inflammation.
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