Mechanisms involved in the antiplatelet activity of Escherichia coli lipopolysaccharide in human platelets.
In this study, Escherichia coli lipopolysaccharide (LPS) dose-dependently (100-300 microg/ml) and time-dependently (10-60 min) inhibited platelet aggregation in human platelets stimulated by agonists. LPS also dose-dependently inhibited the phosphoinositide breakdown and the intracellular Ca+2 mobilization in human platelets stimulated by collagen. LPS (300 microg/ml) also significantly inhibited the thromboxane A2 formation stimulated by collagen in human platelets. Moreover, LPS (100-300 microg/ml) dose-dependently decreased the fluorescence of platelet membranes tagged with diphenylhexatrience. In addition, LPS (200 and 300 microg/ml) significantly increased the formation of cyclic GMP but not cyclic AMP in platelets. LPS (200 microg/ml) also significantly increased the production of nitrate within a 30 min incubation period. Rapid phosphorylation of a platelet protein of Mr 47,000, a marker of protein kinase C activation, was triggered by phorbol-12-13-dibutyrate (PDBu, 50 nM). This phosphorylation was markedly inhibited by LPS (200 microg/ml) within a 30 min incubation period. These results indicate that the antiplatelet activity of LPS may be involved in two important pathways. (1) LPS may induce conformational changes in the platelet membrane, leading to change in the activity of phospholipase C. (2) LPS also activated the formation of nitric oxide (NO)/cyclic GMP in human platelets, resulting in inhibition of platelet aggregation. Therefore, LPS-mediated alteration of platelet function may contribute to bleeding diathesis in septicaemic and endotoxaemic patients.
Sheu
J R
JR
Graduate Institute of Medical Sciences, Taipei Medical College, Taiwan.
Hung
W C
WC
Kan
Y C
YC
Lee
Y M
YM
Yen
M H
MH
D001792:Blood Platelets / Q000187:drug effects*; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004926:Escherichia coli; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism
D008070:Lipopolysaccharides; D010716:Phosphatidylinositols; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D009569:Nitric Oxide; D013929:Thromboxane B2; D003094:Collagen; D000242:Cyclic AMP; D011493:Protein Kinase C; D006152:Cyclic GMP