Lipoxins and novel 15‐epi‐lipoxin analogs display potent anti‐inflammatory actions after oral administration

Abstract

1 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 LXA 4 and LXB 4 , 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. 2 LXA 4 , LXB 4 , ATLa2, and ZK-994 were orally active, exhibiting potent systemic inhibition of zymosan A-induced peritonitis at very low doses (50 ng kg À1-50 mg kg À1 ). 3 Intravenous ZK-994 and ZK-142 (500 mg kg À1) potently attenuated hind limb ischemia/ reperfusion-induced lung injury, with 32712 and 5375% inhibition (Po0.05), respectively, of neutrophil accumulation in lungs. The same dose of ATLa2 had no significant protective action. 4 Topical application of ATLa2, ZK-994, and ZK-142 (B20 mg cm À2) prevented vascular leakage and neutrophil infiltration in LTB 4 /PGE 2 -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. 5 In summary, native LXA 4 and LXB 4 , and analogs ATLa2, ZK-142, and ZK-994 retain broad antiinflammatory 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.

Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase–dependent lipoxin production

“…Although this observation does not rule out the possible participation of other 5-LO-dependent mediators, it demonstrates that a deficiency in lipoxins is sufficient to explain the effects on bacterial growth and host response seen in the infected 5-LO-deficient animals. ATLa2 treatment has previously been shown to reduce inflammatory cell infiltration in a number of different disease models (17)(18)(19). Although this subject is not directly addressed in the present article, it is probable that the observed effects of ATLa2 reconstitution in our experiments result from decreased effector cell recruitment into infected lung.…”

“…To address this issue, we administered a stable lipoxin analog, ATLa2, to both WT controls and 5-LO-deficient mice during the first 21 days after infection. This eicosanoid analog, created by design modification of the ω end of LXA 4 , was shown to have increased half-life in vivo and to inhibit inflammation in several disease models (17)(18)(19). As shown in Figure 6, A and B, ATLa2 treatment abrogated the enhanced control of bacterial growth in both lungs and spleens of 5-LO-deficient mice.…”

“…ATLa2, 15-epi-16-phenoxy-parafluoro-LXA4-methyl ester (a generous gift from J. Parkinson, Berlex Biosciences, Richmond, California, USA), was used in vivo as a stable lipoxin analog as previously reported (18). It was administered by gavage 3 times a week at a dose of 0.2 ml (100 ng/animal/treatment) as previously described (19). Treatment was started 2 days after infection and continued until day 20.…”

Long-chain polyunsaturated fatty acids: Selected mechanisms of action on bone

“…Lipoxygenase (LOX) generated lipid mediators (resolvins, lipoxins, protectins and docosanoids) have both anti-inflammatory and pro-resolving activities [120,121]. Both resolvins and lipoxins inhibit inflammation-induced bone resorption and may therefore provide a mechanism by which the n-3 PUFAs protect against bone loss.…”

Lipoxin A4inhibits immune cell binding to salivary epithelium and vascular endothelium

“…LX are formed via two sequential lipoxygenasecatalyzed oxygenations of arachidonic acid (7). LX formation mainly occurs by heterotypic transcellular synthesis between polymorphonuclear leukocytes (PMN) with platelets, endothe-lia, and epithelia during inflammation (79).…”