Design of lipoxin A sub(4) stable analogs that block transmigration and adhesion of human neutrophils

• Published in: Biochemistry (Easton) Vol. 34; no. 44; pp. 14609 - 14615
• Main Authors: Serhan, C N, Maddox, J F, Petasis, NA, Akritopoulou-Zanze, I, Papayianni, A, Brady, H R, Colgan, S P, Madara, J L
• Format: Journal Article
• Language: English
• Published: 01.01.1995
• ISSN: 0006-2960

Lipoxins (LX) are bioactive eicosanoids that carry a tetraene structure and serve as regulators of inflammation, in part by inhibiting neutrophil migration and adhesion. Lipoxin A sub(4) is rapidly regulated by conversion to inactive LX metabolites via local metabolism that involves dehydrogenation as the predominant route. Here, several LXA sub(4) analogs were designed that resisted rapid conversion by both differentiated HL-60 cells and recombinant 15-hydroxyprostaglandin dehydrogenase, systems where native LXA sub(4) is degraded within minutes. The rank order of conversion by recombinant dehydrogenase was LXA sub(4) methyl ester > PGE sub(2) approximately PGE sub(2) methyl ester > LXA sub(4) > > > the novel LXA sub(4) analogs. In addition, 15(R/S)-methyl-LXA sub(4), 15-cyclohexyl-LXA sub(4), and 16-phenoxy-LXA sub(4) proved to retain LXA sub(4) bioactivity and inhibited neutrophil transmigration across polarized epithelial cell monolayers as well as adhesion to vascular endothelial cells. These results indicate that LXA sub(4) analogs can be designed using these criteria to resist rapid transformation and to retain biological actions of native LXA sub(4). Moreover, the results suggest that LXA sub(4) stable analogs can be useful tools both in vitro and in vivo to evaluate LXA sub(4) actions and therapeutic potential.