British Journal of Pharmacology, September 2004
Gerard Bannenberg, Rose-Laure Moussignac, Karsten Gronert, Pallavi R Devchand, Birgitta A Schmidt, William J Guilford, John G Bauman, Babu Subramanyam, H Daniel Perez, John F Parkinson, and Charles N Serhan
Lipoxins (LX) and aspirin-triggered 15-epi-lipoxins (ATL) exert potent anti-inflammatory actions. In the present study, we determined the anti-inflammatory efficacy of endogenous LXA4 and LXB4, the stable ATL analog ATLa2, and a series of novel 3-oxa-ATL analogs (ZK-996, ZK-990, ZK-994, and ZK-142) after intravenous, oral, and topical administration in mice.
LXA4, LXB4, ATLa2, and ZK-994 were orally active, exhibiting potent systemic inhibition of zymosan A-induced peritonitis at very low doses (50 ng kg−1–50 μg kg−1).
Intravenous ZK-994 and ZK-142 (500 μg kg−1) potently attenuated hind limb ischemia/reperfusion-induced lung injury, with 32±12 and 53±5% inhibition (P<0.05), respectively, of neutrophil accumulation in lungs. The same dose of ATLa2 had no significant protective action.
Topical application of ATLa2, ZK-994, and ZK-142 (∼20 μg cm−2) prevented vascular leakage and neutrophil infiltration in LTB4/PGE2-stimulated ear skin inflammation. While ATLa2 and ZK-142 displayed approximately equal anti-inflammatory efficacy in this model, ZK-994 displayed a slower onset of action.
In summary, native LXA4 and LXB4, and analogs ATLa2, ZK-142, and ZK-994 retain broad anti-inflammatory effects after intravenous, oral, and topical administration. The 3-oxa-ATL analogs, which have enhanced metabolic and chemical stability and a superior pharmacokinetic profile, provide new opportunities to explore the actions and therapeutic potential for LX and ATL.
When given orally in an animal model, pro-resolving mediators demonstrate strong efficacy