NEUTROPHIL-MEDIATED CHANGES IN VASCULAR-PERMEABILITY ARE INHIBITED BYTOPICAL APPLICATION OF ASPIRIN-TRIGGERED 15-EPI-LIPOXIN A(4) AND NOVEL LIPOXIN B-4 STABLE ANALOGS

Neutrophil (PMN) activation is critical in inflammation and reperfusio n injury, suggesting that PMN-directed therapies may be of clinical us e. Here, leukotriene B-4 (LTB4)-induced PMN influx in ear skin was equ ivalent between 5-lipoxygenase knockout and wild-type mice, To explore actions of lipoxin (LX) in PMN-mediated tissue injury, we prepared se veral novel LX stable analogues, including analogues of LXA(4) and asp irin-triggered 15-epi-LXA(4) as well as LXB4, and examined their impac t in PMN infiltration and vascular permeability. Each applied topicall y to mouse ears inhibited dramatically PMN-mediated increases in vascu lar permeability (IC50 range of 13-26 nmol) with a rank order of 15(R/ S)-methyl-LXA(4) > 16-para-fluoro-phenoxy-LXA(4) similar to 5(S)-methy l-LXB4 greater than or equal to 16-phenoxy-LXA(4) > 5(R)-methyl-LXB4. These LX mimetics were as potent as an LTB, receptor antagonist, yet r esults from microphysiometry with mouse leukocytes indicated that they do not act as LTB, receptor level antagonists. In addition, within 24 h of delivery, > 90% were cleared from ear biopsies, Neither IL-8, FM LP, C5a, LTD4, nor platelet-activating factor act topically to promote PMN influx. When applied with LTB4, PGE(2) enhanced sharply both infi ltration and vascular permeability, which were inhibited by a fluorina ted stable analogue of aspirin-triggered LX. These results indicate th at mimetics of LXs and aspirin-triggered 15-epi-LXA(4) are topically a ctive in this model and are potent inhibitors of both PMN infiltration and PMN-mediated vascular injury.