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* Research Business Area Dermatology, Research Laboratories, Schering AG, Berlin, Germany;
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and Departments of
Medicinal Chemistry and
Immunology, Berlex Biosciences, Richmond, CA 94804
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 A4
analog, 15-epi-16-p-fluorophenoxy-lipoxin
A4 methyl ester (ATLa), was synthesized by total organic
synthesis and examined for efficacy relative to a potent leukotriene
B4 (LTB4) receptor antagonist
(LTB4R-Ant) and the clinically used topical glucocorticoid
methylprednisolone aceponate. In vitro, ATLa was 100-fold more potent
than LTB4R-Ant for inhibiting neutrophil chemotaxis and
trans-epithelial cell migration induced by fMLP, but was
10-fold less potent than the LTB4R-Ant in blocking
responses to LTB4. 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 LTB4R-Ant
and methylprednisolone aceponate. ATLa was efficacious in all models
tested: LTB4/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 LXA4 and
aspirin-triggered LXA4 pathways play key
anti-inflammatory roles in vivo. Moreover, these results suggest
that ATLa and related LXA4 analogs may have broad
therapeutic potential in inflammatory disorders and could provide an
alternative to corticosteroids in certain clinical
settings.
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