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 A4 (ATLa1)] and the omega end [15-epi-16-(para-fluoro)-phenoxy-LXA4 (ATLa2)] were recoverable to approximately 90 and 100% at 3 hr, respectively, compared with a approximately 40% loss of native lipoxin A4. ATLa2 retains bioactivity and, at levels as low as approximately 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 (approximately 77% inhibition) or systemic delivery by intravenous injection (approximately 85% inhibition) and proved more potent than local delivery of ASA. Rank order for inhibiting polymorphonuclear leukocyte infiltration was: ATLa2 (10 micrograms, i.v.) approximately ATLa2 (10 micrograms, local) approximately dexamethasone (10 micrograms, local) >ASA (1.0 mg, local). Applied topically to mouse ear skin, ATLa2 also inhibited polymorphonuclear leukocyte infiltration induced by leukotriene B4 (approximately 78% inhibition) or phorbol ester (approximately 49% inhibition), which initiates endogenous chemokine production. These results indicate that this fluorinated analog of natural aspirin-triggered lipoxin A4 is bioavailable by either local or systemic delivery routes and is a more potent and precise inhibitor of neutrophil accumulation than is ASA.
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
C B
CB
Clish
J A
JA
O'Brien
K
K
Gronert
G L
GL
Stahl
N A
NA
Petasis
C N
CN
Serhan
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte; D004423:Ear; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood*; D044045:Lipoxins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000503:physiopathology; D012879:Skin Physiological Phenomena; D013237:Stereoisomerism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology
D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D001241:Aspirin