Aspirin-triggered 15-Epi-Lipoxin A(4) (LXA(4)) and LXA(4) Stable Analogues Are Potent Inhibitors of Acute Inflammation: Evidence for Anti-inflammatory Receptors

Lipoxins are bioactive eicosanoids that are immunomodulators. In human myeloid cells, lipoxin (LX) A(4) actions are mediated by interaction with a G protein–coupled receptor. To explore functions of LXA(4) and aspirin-triggered 5(S),6(R),15(R)-trihydroxy-7,9,13-trans-11-cis–eicosatetraenoic acid (15-epi-LXA(4)) in vivo, we cloned and characterized a mouse LXA(4) receptor (LXA(4)R). When expressed in Chinese hamster ovary cells, the mouse LXA(4)R showed specific binding to [(3)H]LXA(4 )(K (d) ≈ 1.5 nM), and with LXA(4 )activated GTP hydrolysis. Mouse LXA(4)R mRNA was most abundant in neutrophils. In addition to LXA(4) and 15-epi-LXA(4), bioactive LX stable analogues competed with both [(3)H]LXA(4) and [(3)H]leukotriene D(4) (LTD(4))– specific binding in vitro to neutrophils and endothelial cells, respectively. Topical application of LXA(4) analogues and novel aspirin-triggered 15-epi-LXA(4) stable analogues to mouse ears markedly inhibited neutrophil infiltration in vivo as assessed by both light microscopy and reduced myeloperoxidase activity in skin biopsies. The 15(R)-16-phenoxy-17,18, 19,20-tetranorLXA(4 )methyl ester (15-epi-16-phenoxy-LXA(4)), an analogue of aspirin triggered 15-epi-LXA(4), and 15(S)-16-phenoxy-17,18,19,20-tetranor-LXA(4) methyl ester (16-phenoxy-LXA(4)) were each as potent as equimolar applications of the anti-inflammatory, dexamethasone. Thus, we identified murine LXA(4)R, which is highly expressed on murine neutrophils, and showed that both LXA(4) and 15-epi-LXA(4) stable analogues inhibit neutrophil infiltration in the mouse ear model of inflammation. These findings provide direct in vivo evidence for an anti-inflammatory action for both aspirin-triggered LXA(4) and LXA(4) stable analogues and their site of action in vivo.