An aspirin-triggered lipoxin A4 stable analog displays a unique topical anti-inflammatory profile.
Lipoxins and 15-epi-lipoxins are counter-regulatory lipid mediators that modulate leukocyte trafficking and promote the resolution of inflammation. To assess the potential of lipoxins as novel anti-inflammatory agents, a stable 15-epi-lipoxin A(4) analog, 15-epi-16-p-fluorophenoxy-lipoxin A(4) methyl ester (ATLa), was synthesized by total organic synthesis and examined for efficacy relative to a potent leukotriene B(4) (LTB(4)) receptor antagonist (LTB(4)R-Ant) and the clinically used topical glucocorticoid methylprednisolone aceponate. In vitro, ATLa was 100-fold more potent than LTB(4)R-Ant for inhibiting neutrophil chemotaxis and trans-epithelial cell migration induced by fMLP, but was approximately 10-fold less potent than the LTB(4)R-Ant in blocking responses to LTB(4). A broad panel of cutaneous inflammation models that display pathological aspects of psoriasis, atopic dermatitis, and allergic contact dermatitis was used to directly compare the topical efficacy of ATLa with that of LTB(4)R-Ant and methylprednisolone aceponate. ATLa was efficacious in all models tested: LTB(4)/Iloprost-, calcium ionophore-, croton oil-, and mezerein-induced inflammation and trimellitic anhydride-induced allergic delayed-type hypersensitivity. ATLa was efficacious in mouse and guinea pig skin inflammation models, exhibiting dose-dependent effects on edema, neutrophil or eosinophil infiltration, and epidermal hyperproliferation. We conclude that the LXA(4) and aspirin-triggered LXA(4) pathways play key anti-inflammatory roles in vivo. Moreover, these results suggest that ATLa and related LXA(4) analogs may have broad therapeutic potential in inflammatory disorders and could provide an alternative to corticosteroids in certain clinical settings.
Schottelius
Arndt J
AJ
Research Business Area Dermatology, Research Laboratories, Schering AG, Berlin, Germany.
Giesen
Claudia
C
Asadullah
Khusru
K
Fierro
Iolanda M
IM
Colgan
Sean P
SP
Bauman
John
J
Guilford
William
W
Perez
Hector D
HD
Parkinson
John F
JF
D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000378:metabolism* / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D000001:Calcimycin / Q000633:toxicity; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003436:Croton Oil / Q000633:toxicity; D004195:Disease Models, Animal; D004224:Diterpenes; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000008:administration & dosage* / Q000378:metabolism* / Q000494:pharmacology; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000517:prevention & control; D016285:Iloprost / Q000037:antagonists & inhibitors / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000633:toxicity; D044045:Lipoxins; D051379:Mice; D010796:Phthalic Anhydrides / Q000633:toxicity; D012867:Skin / Q000187:drug effects* / Q000473:pathology*; D013729:Terpenes / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; D010796:Phthalic Anhydrides; D013729:Terpenes; C040527:lipoxin A4; D007975:Leukotriene B4; C011309:mezerein; D000001:Calcimycin; D003436:Croton Oil; C015559:trimellitic anhydride; D016285:Iloprost; D001241:Aspirin