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Am J Physiol Cell Physiol 276: C988-C994, 1999;
0363-6143/99 $5.00
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Vol. 276, Issue 4, C988-C994, April 1999

RAPID COMMUNICATION
LXA4, aspirin-triggered 15-epi-LXA4, and their analogs selectively downregulate PMN azurophilic degranulation

Andrew T. Gewirtz1, Valery V. Fokin2, Nicos A. Petasis2, Charles N. Serhan3, and James L. Madara1

1 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia; 2 Department of Chemistry, University of Southern California, Los Angeles, California; and 3 Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

The eicosanoid lipoxin A4 (LXA4) is biosynthesized in vivo by cells present at inflammatory sites and appears to be an endogenous anti-inflammatory mediator. Further, in the presence of aspirin, the 15-epimer of LXA4 (15-epi-LXA4) is biosynthesized and may mediate some of aspirin's desirable bioactions. LXA4, 15-epi-LXA4, and their stable analogs inhibit inflammation in established animal models, indicating that these compounds may be useful for treating inflammatory disease states. To investigate the cellular mechanisms by which these lipid mediators downregulate inflammation, we investigated whether these eicosanoids could influence receptor-mediated degranulation of human neutrophils, an event thought to play a major causative role in several inflammatory disease states. LXA4, 15-epi-LXA4, and their stable analogs potently (IC50 < 1 nM) and selectively downregulated neutrophil release of azurophilic granule contents but did not affect other neutrophil secretory functions. Thus the cellular basis of action of these natural off-switches to inflammation appears to involve downregulation of neutrophil azurophilic granule release.

anti-inflammatory mediators; elastase; eicosanoids; Fcgamma receptors; immune complexes; neutrophils


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