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.
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Boston, MA, USA.
Gerard
G
Bannenberg
Rose-Laure
RL
Moussignac
Karsten
K
Gronert
Pallavi R
PR
Devchand
Birgitta A
BA
Schmidt
William J
WJ
Guilford
John G
JG
Bauman
Babu
B
Subramanyam
H Daniel
HD
Perez
John F
JF
Parkinson
Charles N
CN
Serhan
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