Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo

Aspirin (ASA) triggers a switch in the biosynthesis of lipid mediators, inhibiting prostanoid production and initiating 15-epi-lipoxin generation through the acetylation of cyclooxygenase II. These aspirin-triggered lipoxins (ATL) may mediate some of ASA's beneficial actions and therefore are of interest in the search for novel antiinflammatories that could manifest fewer unwanted side effects. Here, we report that design modifications to native ATL structure prolong its biostability in vivo. In mouse whole blood, ATL analogs protected at carbon 15 [15(R/S)-methyl-lipoxin A(4) (ATLa(1))] and the omega end [15-epi-16-(parafluoro)-phenoxy-LXA(4) (ATLa(2))] were recoverable to approximate to 90 and 100% at 3 hr, respectively, compared with a approximate to 40% loss of native lipoxin A(4). ATLa(2) retains bioactivity and, at levels as low as approximate to 24 nmol/mouse, potently inhibited tumor necrosis factor-alpha-induced leukocyte recruitment into the dorsal air pouch. Inhibition was evident by either local intra-air pouch delivery (approximate to 77% inhibition) or systemic delivery by intravenous injection (approximate to 85% inhibition) and proved more potent than local delivery of ASA. Rank order for inhibiting polymorphonuclear leukocyte infiltration was: ATLa(2) (10 mu g, i.v.) approximate to ATLa(2) (10 mu g, local) approximate to dexamethasone (10 mu g, local) >ASA (1.0 mg, local). Applied topically to mouse ear skin, ATLa(2) also inhibited polymorphonuclear leukocyte infiltration induced by leukotriene B-4 (approximate to 78% inhibition) or phorbol ester (approximate to 49% inhibition), which initiates endogenous chemokine production. These results indicate that this fluorinated analog of natural aspirin-triggered lipoxin A(4) is bioavailable by either local or systemic delivery routes and is a more potent and precise inhibitor of neutrophil accumulation than is ASA.