Platelet-activating factor synthesis by peritoneal mast cells and its inhibition by two quinoline-based compounds.
1. Peritoneal mast cells from rat were co-incubated in vitro in a platelet aggregometer cuvette with washed rabbit platelets. In response to stimulation with calcium ionophore (A23187; 1-5 microM), the mast cells released a substance which stimulated the platelets to aggregate. These concentrations of ionophore did not stimulate platelet aggregation in the absence of mast cells, nor affect the responsiveness of the platelets to aggregation induced by thrombin or PAF. Release of a PAF-like substance was also observed in response to stimulation of the mast cells with antigen. 2. This pro-aggregatory activity is attributable to the release of PAF by the mast cells, since the activity could be abolished by preincubating the platelets with a specific PAF receptor antagonist (WEB 2086; 10 microM). Furthermore, the platelet-aggregating factor co-migrated with PAF on thin-layer chromatographs and could be abolished by incubation with phospholipase A2 (20 micrograms ml-1) or a specific antibody directed against PAF. 3. The release of PAF by peritoneal mast cells could be inhibited, in a concentration-dependent manner, by PF-5901 (IC50 of 3.9 microM) or Wy-50,295 (IC50 of 1.2 microM), two structurally similar compounds with inhibitory effects on leukotriene synthesis, as well as leukotriene D4 (LTD4) receptor antagonist properties. 4. Inhibition of PAF synthesis was not observed when the mast cells were incubated with a structurally unrelated 5-lipoxygenase inhibitor (A-64077), a structurally dissimilar inhibitor of 5-lipoxygenase activating protein (MK-886) or with a structurally related LTD4 receptor antagonist (MK-571) which lacks inhibitory effects on leukotriene synthesis, each at concentrations of up to 100 microM.5. Neither PF-5901 nor Wy-50,295 (1 or 10 microM) significantly affected histamine release or prostaglandin D2 synthesis by peritoneal mast cells in response to calcium ionophore stimulation.6. These results demonstrate the ability of a class of quinoline-based compounds to inhibit PAF synthesis by peritoneal mast cells. This activity does not appear to be related to effects of these compounds on leukotriene synthesis or LTD4 receptors. The ability of these compounds to inhibit PAF synthesis may contribute to their anti-inflammatory properties.
Hogaboam
C M
CM
Gastrointestinal and Immunological Sciences Research Group, University of Calgary, Alberta, Canada.
Donigi-Gale
D
D
Shoupe
T S
TS
Bissonnette
E Y
EY
Befus
A D
AD
Wallace
J L
JL
D000818:Animals; D001681:Biological Assay; D000001:Calcimycin / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D009280:Naphthaleneacetic Acids / Q000494:pharmacology*; D010529:Peritoneal Cavity / Q000166:cytology*; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D010974:Platelet Aggregation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D016859:Lipoxygenase Inhibitors; D009280:Naphthaleneacetic Acids; D010972:Platelet Activating Factor; D011804:Quinolines; C049740:alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; C067525:S(alpha)-methyl-6-(2-quinolinylmethoxy)-2-naphthaleneacetic acid; D000001:Calcimycin; D006632:Histamine; D015230:Prostaglandin D2