Neutrophil Adherence to Bladder Microvascular Endothelial Cells following Platelet-Activating Factor Acetylhydrolase Inhibition

  1. Suzanne M. Vinson,
  2. Alice Rickard,
  3. Jan S. Ryerse and
  4. Jane McHowat
  1. Department of Pathology, St. Louis University School of Medicine, St. Louis, Missouri
  1. Address correspondence to:
    Dr. Jane McHowat, Department of Pathology, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104. E-mail: jane.mchowat{at}tenethealth.com

Abstract

Interstitial cystitis (IC) is an inflammatory bladder condition of unknown etiology. Tryptase released from elevated numbers of activated mast cells is a proposed mediator of the inflammatory process in IC. We have previously shown that tryptase increases human bladder microvascular endothelial cell (HBMEC) calcium-independent phospholipase A2 (iPLA2) activity, resulting in the production of multiple biologically active phospholipid metabolites, including platelet-activating factor (PAF), that can mediate inflammation. Because the design of selective PLA2 inhibitors may provide a useful therapeutic strategy to reduce the inflammatory process in IC, we tested several frequently used PLA2 inhibitors on PAF production in tryptase-stimulated HBMEC. Among the inhibitors tested, methyl arachidonyl fluorophosphonate (MAFP) was found to be a potent inhibitor of PAF-acetylhydrolase activity. Pretreatment of HBMEC with MAFP significantly increased PAF production in both unstimulated and tryptase-stimulated cells. In addition, MAFP pretreatment of tryptase-stimulated HBMEC increased both surface expression of P-selectin and polymorphonuclear leukocyte adherence to the HBMEC monolayer. These effects suggest that MAFP has a proinflammatory effect, irrespective of its ability to inhibit PLA2.

Footnotes

  • This research was supported by the National Institutes of Health Grant DK-66119 (to J.M.) and was previously presented at the 2005 Federation of American Societies for Experimental Biology meeting, San Diego, CA, Mar 31-Apr 5.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.105.085365.

  • ABBREVIATIONS: IC, interstitial cystitis; HBMEC, human bladder microvascular endothelial cell(s); iPLA2, calcium-independent phospholipase A2; PAF, platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine); PMN, polymorphonuclear leukocyte(s); lysoPlsEtn, lysoplasmenylethanolamine; PAF-AH, platelet-activating factor-acetylhydrolase; MAFP, methyl arachidonyl fluorophosphonate; cPLA2, cytosolic PLA2; BEL, bromoenol lactone [(E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one]; AACOCF3, arachidonyl trifluoromethyl ketone; PX-18, 2-[N,N-bis(2-oleoyloxyethyl)amine]-1-ethanesulfonic acid; MPO, myeloperoxidase; SEM, scanning electron microscopy; sPLA2, secreted phospholipase A2.

    • Received February 23, 2005.
    • Accepted June 2, 2005.
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  1. Published online before print June 3, 2005, doi: 10.1124/jpet.105.085365 JPET September 2005 vol. 314 no. 3 1241-1247
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