Defibrotide in vitro inhibits neutrophil activation by a Ca++-involving mechanism.
Defibrotide, a polydeoxyribonucleotide provided with a pro-fibrinolytic and prostacyclin-like activity, was studied as an inhibitor of polymorphonuclear leucocyte activation in vitro. It was found capable of dose-dependently (1-8 X 10(-5) M) inhibiting FMLP-induced activation, as shown by a decrease of enzyme release and free-radical formation (superoxide anion generation and chemiluminescence). A similar inhibiting activity was observed on A23187-induced activation. An increase in extracellular Ca++ concentration significantly prevented the effect of defibrotide on ionophore stimulation. When PMA was employed as stimulating agent, the drug did not show any inhibiting effect. Finally the pre-treatment of cells with theophylline markedly reduced the inhibition by defibrotide of FMLP- and A23187-dependent activation. Since the stimulation of neutrophils by FMLP and A23187 depends on the increase of cytoplasmic free-calcium availability or extracellular calcium entrance respectively, whereas PMA activation is completely independent from any Ca++ change, the inhibiting effect of defibrotide could be attributed to a Ca++-involving mechanism.
Di Perri
T
T
Institute of Medical Pathology, University of Siena, Italy.
Laghi Pasini
F
F
Capecchi
P L
PL
Ceccatelli
L
L
Pasqui
A L
AL
Orrico
A
A
D002118:Calcium / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005609:Free Radicals; D006801:Humans; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D009113:Muramidase / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D013806:Theophylline / Q000494:pharmacology
D005343:Fibrinolytic Agents; D005609:Free Radicals; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D013806:Theophylline; D009113:Muramidase; D002118:Calcium