Lipoxins and novel 15-epi-lipoxin analogs display potent anti-inflammatory actions after oral administration.
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(-1)-50 microg kg(-1)). 3. Intravenous ZK-994 and ZK-142 (500 microg 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. 4. Topical application of ATLa2, ZK-994, and ZK-142 ( approximately 20 microg cm(-2)) 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 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.
Bannenberg
Gerard
G
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Boston, MA, USA.
Moussignac
Rose-Laure
RL
Gronert
Karsten
K
Devchand
Pallavi R
PR
Schmidt
Birgitta A
BA
Guilford
William J
WJ
Bauman
John G
JG
Subramanyam
Babu
B
Perez
H Daniel
HD
Parkinson
John F
JF
Serhan
Charles N
CN
D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D004431:Ear, External / Q000473:pathology; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D007275:Injections, Intravenous; D044045:Lipoxins / Q000008:administration & dosage / Q000494:pharmacology*; D008171:Lung Diseases / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D010538:Peritonitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D015054:Zymosan / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D044045:Lipoxins; C040527:lipoxin A4; D015054:Zymosan; D001241:Aspirin