Neutrophil adherence to bladder microvascular endothelial cells following platelet-activating factor acetylhydrolase inhibition.
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 A(2) (iPLA(2)) 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 PLA(2) inhibitors may provide a useful therapeutic strategy to reduce the inflammatory process in IC, we tested several frequently used PLA(2) 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 PLA(2).
Vinson
Suzanne M
SM
Department of Pathology, St. Louis University School of Medicine, MO 63104, USA.
Rickard
Alice
A
Ryerse
Jan S
JS
McHowat
Jane
J
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors*; D001095:Arachidonic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003556:Cystitis / Q000188:drug therapy / Q000209:etiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009504:Neutrophils / Q000502:physiology*; D063065:Organophosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000502:physiology; D010972:Platelet Activating Factor / Q000096:biosynthesis; D001743:Urinary Bladder / Q000098:blood supply*
D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D010972:Platelet Activating Factor; C104810:methyl arachidonylfluorophosphonate; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase