Comparison of 1-O-alkyl-, 1-O-alk-1'-enyl-, and 1-O-acyl-2-acetyl-sn-glycero-3-phosphoethanolamines and -3-phosphocholines as agonists of the platelet-activating factor family.
Four naturally occurring platelet-activating factor (PAF) analogs, 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphocholine, 1-hexadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, 1-octadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, and 1-alkyl-2-acetyl-sn-glycero-3-phosphoethanolamine, stimulated human neutrophils (PMN) to mobilize Ca2+, degranulate, and produce superoxide anion. They were, respectively, 5-, 300-, 500-, and 4000-fold weaker than PAF in each assay; inhibited PMN-binding of [3H]PAF at concentrations paralleling their biological potencies; and showed sensitivity to the inhibitory effects of PAF antagonists. PAF and the analogs, moreover, desensitized PMN responses to each other but not to leukotriene B4 and actually increased (or primed) PMN responses to N-formyl-MET-LEU-PHE. Finally, 5-hydroxyeicosatetraenoate-enhanced PMN responses to PAF and the analogs without enhancing the actions of other stimuli. It stereospecifically raised each analog's potency by as much as 100-fold and converted a fifth natural analog, 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine from inactive to a weak stimulator of PMN. PAF and its analogs thus represent a structurally diverse family of cell-derived phospholipids which can activate, prime, and desensitize neutrophils by using a common, apparently PAF receptor-dependent mechanism.
O'Flaherty
J T
JT
Department of Medicine, Wake Forest University, Bowman Gray School of Medicine, Winston-Salem, NC 27106.
Tessner
T
T
Greene
D
D
Redman
J R
JR
Wykle
R L
RL
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D010955:Plasmalogens / Q000138:chemical synthesis / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism
D006893:Hydroxyeicosatetraenoic Acids; D010955:Plasmalogens; D010972:Platelet Activating Factor; C020791:phosphatidal ethanolamines; D013481:Superoxides; C055475:1-O-hexadec-1'-enyl-2-acetyl-sn-glycero-3-phosphocholine; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D002118:Calcium