       Document 0200
 DOCN  M9610200
 TI    Aspirin triggers previously undescribed bioactive eicosanoids by human
       endothelial cell-leukocyte interactions.
 DT    9601
 AU    Claria J; Serhan CN; Department of Medicine, Brigham and Women's
       Hospital, Boston, MA,; USA.
 SO    Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9475-9. Unique Identifier :
       AIDSLINE MED/96003801
 AB    Aspirin [acetylsalicylic acid (ASA)], along with its
       analgesic-antipyretic uses, is now also being considered for
       cardiovascular protection and treatments in cancer and human
       immunodeficiency virus infection. Although many of ASA's pharmacological
       actions are related to its ability to inhibit prostaglandin and
       thromboxane biosynthesis, some of its beneficial therapeutic effects are
       not completely understood. Here, ASA triggered transcellular
       biosynthesis of a previously unrecognized class of eicosanoids during
       coincubations of human umbilical vein endothelial cells (HUVEC) and
       neutrophils [polymorphonuclear leukocytes (PMN)]. These eicosanoids were
       generated with ASA but not by indomethacin, salicylate, or
       dexamethasone. Formation was enhanced by cytokines (interleukin 1 beta)
       that induced the appearance of prostaglandin G/H synthase 2 (PGHS-2) but
       not 15-lipoxygenase, which initiates their biosynthesis from arachidonic
       acid in HUVEC. Costimulation of HUVEC/PMN by either thrombin plus the
       chemotactic peptide fMet-Leu-Phe or phorbol 12-myristate 13-acetate or
       ionophore A23187 leads to the production of these eicosanoids from
       endogenous sources. Four of these eicosanoids were also produced when
       PMN were exposed to 15R-HETE
       [(15R)-15-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid] and an
       agonist. Physical methods showed that the class consists of four
       tetraene-containing products from arachidonic acid that proved to be
       15R-epimers of lipoxins. Two of these compounds (III and IV) were potent
       inhibitors of leukotriene B4-mediated PMN adhesion to HUVEC, with
       compound IV
       [(5S,6R,15R)-5,6,15-trihydroxy-7,9,13-trans-11-cis-eicosatetraeno- i c
       acid; 15-epilipoxin A4] active in the nanomolar range. These results
       demonstrate that ASA evokes a unique class of eicosanoids formed by
       acetylated PGHS-2 and 5-lipoxygenase interactions, which may contribute
       to the therapeutic impact of this drug. Moreover, they provide an
       example of a drug's ability to pirate endogenous biosynthetic mechanisms
       to trigger new mediators.
 DE    Arachidonate 15-Lipoxygenase/ANALYSIS  Aspirin/*PHARMACOLOGY
       Calcimycin/PHARMACOLOGY  Carboxypeptidases/PHARMACOLOGY  Cell
       Communication/*DRUG EFFECTS  Cells, Cultured  Chromatography, High
       Pressure Liquid  Drug Interactions  Eicosanoids/*BIOSYNTHESIS
       Endothelium, Vascular/*DRUG EFFECTS  Enzyme-Linked Immunosorbent Assay
       Human  Interleukin-1/PHARMACOLOGY  Mass Fragmentography
       Neutrophils/*DRUG EFFECTS  Prostaglandin-Endoperoxide Synthase/ANALYSIS
       Support, Non-U.S. Gov't  Support, U.S. Gov't, Non-P.H.S.  Support, U.S.
       Gov't, P.H.S.  Tetradecanoylphorbol Acetate/PHARMACOLOGY
       Thrombin/PHARMACOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

