Platelet-activating factor stimulates secretion of respiratory glycoconjugate from human airways in culture.
Platelet-activating factor (PAF) is a naturally occurring phospholipid that acts as a potent mediator of inflammation and bronchoconstriction. Since mucus secretion accompanies many pulmonary-allergic reactions, we examined the effect of PAF on respiratory glycoconjugate (RGC) release from human airways in vitro. PAF, in concentrations of 5 to 100 ng/ml, induced a specific, dose-dependent release of [3H]RGC from human airways in vitro (range of 15% to 120% increase above control, p less than 0.001; n = 8). Time-course studies revealed that RGC release reached its peak level by 60 minutes, and by the end of 4 hours, decreased almost to the baseline level, suggesting a stimulatory effect on secretion rather than synthesis. PAF analog, RO 19-3704, which is a PAF-receptor antagonist, inhibited RGC secretion mediated by PAF in a dose-dependent manner with an inhibitory concentration of 50% of 70 ng/ml. BW 755C and nordihydroguaiaretic acid, but not indomethacin, inhibited RGC release by PAF. LY 171883, a specific leukotriene D4-receptor antagonist, totally inhibited the release of RGC by PAF. Similar results were observed with FPL 55712. PAF-treated airways generated peptidoleukotrienes significantly above control airways in association with enhanced RGC secretion. This enhanced effect on RGC secretion was specifically and significantly blocked by LY 171883. Atropine (10(-5) mol/L) augmented the secretagogue activity of PAF, whereas dexamethasone (10(-5) mol/L) inhibited it. These data indicate that PAF is a significant RGC secretagogue that affects the RGC-secreting cells via the lipoxygenase pathway of arachidonic acid metabolism and the generation of leukotrienes in the airways, but not through the cholinergic receptors on the secretory cells.
Goswami
S K
SK
Mount Sinai Medical Center, Department of Medicine, New York, NY 10029.
Ohashi
M
M
Stathas
P
P
Marom
Z M
ZM
D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D001285:Atropine / Q000494:pharmacology; D001980:Bronchi / Q000378:metabolism*; D046508:Culture Techniques; D016861:Cyclooxygenase Inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005995:Glyceryl Ethers / Q000494:pharmacology; D006001:Glycoconjugates / Q000378:metabolism*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D009092:Mucous Membrane / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D005995:Glyceryl Ethers; D006001:Glycoconjugates; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D013844:Thiazoles; C053235:Ro 19-3704; D001285:Atropine; D003907:Dexamethasone