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

被引：282

作者：

SERHAN, CN

MADDOX, JF

PETASIS, NA

AKRITOPOULOUZANZE, I

PAPAYIANNI, A

BRADY, HR

COLGAN, SP

MADARA, JL

机构：

[1] HARVARD UNIV, SCH MED, BOSTON, MA 02115 USA

[2] UNIV SO CALIF, DEPT CHEM, LOS ANGELES, CA 90089 USA

[3] BRIGHAM & WOMENS HOSP, DEPT MED, DIV RENAL, BOSTON, MA 02115 USA

[4] BRIGHAM & WOMENS HOSP, DEPT PATHOL, BOSTON, MA 02115 USA

[5] BROCKTON W ROXBURY VET AFFAIRS MED CTR, RENAL SECT, BOSTON, MA 02115 USA

来源：

BIOCHEMISTRY | 1995年 / 34卷 / 44期

关键词：

D O I：

10.1021/bi00044a041

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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(4) is rapidly regulated by conversion 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 HL-60 cells and recombinant 15-hydroxyprostaglandin dehydrogenase, systems 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) analogs. In addition, 15(R/S)-methyl-LXA(4), 15-cyclohexyl-LXA(A), and 16-phenoxy-LXA(4) proved to retain LXA(4) bioactivity and inhibited neutrophil 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 rapid 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 therapeutic potential.

引用

页码：14609 / 14615

页数：7

共 39 条

[1]

Anggard E., Samuelsson B., Ark. Kemi, 25, pp. 293-300, (1966)

[2]

Badr K.P., Lakkis F.G., Ann. N. Y. Acad. Sci., 744, pp. 216-228, (1994)

[3]

Belluzzi A., Campieri M., Gionchetti P., Boschi S., Rizzello F., Brignola C., Poggioli G., Bertinelli E., Ferretti M., Miglioli M., Barbara L., Gastroenterology, 106, (1994)

[4]

Boucher J.L., Delaforge M., Mansuy D., Biochem. Biophys. Res. Commun., 177, pp. 134-139, (1991)

[5]

Boyum A., Scand. J. Clin. Lab. Invest., 21, 97, pp. 77-89, (1968)

[6]

Bradford M.M., Anal. Biochem., 72, pp. 248-254, (1916)

[7]

Chavis C., Chanez P., Vachier I., Bousquet J., Michel F.B., Godard P., Biochem. Biophys. Res. Commun., 207, pp. 273-279, (1995)

[8]

Christie P.E., Spur B.W., Lee T.H., Am. Rev. Respir. Dis., 145, pp. 1281-1284, (1992)

[9]

Claria J., Serhan C.N., Proc. Natl. Acad Sci. U.S.A., 92, pp. 9475-9479, (1995)

[10]

Colgan S.P., Serhan C.N., Parkos C.A., Delp-Archer C., Madara J.L., J. Clin. Invest., 92, pp. 75-82, (1993)

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