The membrane attack complex of complement contributes to plasmin-induced synthesis of platelet-activating factor by endothelial cells and neutrophils.
Thrombolytic agents, used to restore blood flow to ischaemic tissues, activate several enzymatic systems with pro-inflammatory effects, thus potentially contributing to the pathogenesis of ischaemia-reperfusion injury. Platelet-activating factor (PAF), a phospholipid mediator of inflammation, has been implicated in the pathogenesis of this process. We previously showed that the infusion of streptokinase (SK) induces the intravascular release of PAF in patients with acute myocardial infarction (AMI), and that cultured human endothelial cells (EC) synthesized PAF in response to SK and plasmin (PLN). In the present study, we investigated the role of the membrane attack complex (MAC) of complement in the PLN-induced synthesis of PAF. In vivo, we showed a correlation between the levels of soluble terminal complement components (sC5b-9) and the concentrations of PAF detected in blood of patients with AMI infused with SK. In vitro both EC and polymorphonuclear neutrophils (PMN), incubated in the presence of PLN and normal human serum, showed an intense staining for the MAC neoepitope, while no staining was detected when they were incubated with PLN in the presence of heat-inactivated normal human serum. Moreover, the insertion of MAC on EC and PMN plasmamembrane elicited the synthesis of PAF. In conclusion, our results elucidate the mechanisms involved in PAF production during the activation of the fibrinolytic system, showing a role for complement products in this setting. The release of PAF may increase the inflammatory response, thus limiting the beneficial effects of thrombolytic therapy. Moreover, it may have a pathogenic role in other pathological conditions, such as transplant rejection, tumoral angiogenesis, and septic shock, where fibrinolysis is activated.
Lupia
Enrico
E
Departments of Clinical Pathophysiology and Internal Medicine, University of Turin, Turin, Italy.
Del Sorbo
Lorenzo
L
Bergerone
Serena
S
Emanuelli
Giorgio
G
Camussi
Giovanni
G
Montrucchio
Giuseppe
G
D002478:Cells, Cultured; D003167:Complement Activation / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000032:analysis / Q000276:immunology*; D004727:Endothelium / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D005260:Female; D005341:Fibrinolysin / Q000276:immunology*; D005342:Fibrinolysis / Q000276:immunology; D019085:Fluorescent Antibody Technique, Direct / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000276:immunology*; D009504:Neutrophils / Q000378:metabolism; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D013300:Streptokinase / Q000008:administration & dosage
D015938:Complement Membrane Attack Complex; D000939:Epitopes; D010972:Platelet Activating Factor; D013300:Streptokinase; D005341:Fibrinolysin