DESIGN OF LIPOXIN A(4) STABLE ANALOGS THAT BLOCK TRANSMIGRATION AND ADHESION OF HUMAN NEUTROPHILS

Lipoxins (LX) are bioactive eicosanoids that carry a tetraene structur e and serve as regulators of inflammation, in part by inhibiting neutr ophil migration and adhesion. Lipoxin A(4) is rapidly regulated by con version to inactive LX metabolites via local metabolism that involves dehydrogenation as the predominant route. Here, several LXA(4) analogs were designed that resisted rapid conversion by both differentiated H L-60 cells and recombinant 15-hydroxyprostaglandin dehydrogenase, syst ems where native LXA(4) is degraded within minutes. The rank order of conversion by recombinant dehydrogenase was LXA(4) methyl ester > PGE( 2) approximate to PGE(2) methyl ester > LXA(4) >>> the novel LXA(4) an alogs. In addition, 15(R/S)-methyl-LXA(4), 15-cyclohexyl-LXA(A), and 1 6-phenoxy-LXA(4) proved to retain LXA(4) bioactivity and inhibited neu trophil transmigration across polarized epithelial cell monolayers as well as adhesion to vascular endothelial cells. These results indicate that LXA(4) analogs can be designed using these criteria to resist ra pid transformation and to retain biological actions of native LXA(4). Moreover, the results suggest that LXA(4) stable analogs can be useful tools both in vitro and in vivo to evaluate LXA(4) actions and therap eutic potential.