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Biao Zeng, David Bruce, Jillian Kril, Victoria Ploplis, Ben Freedman, David Brieger
Influence of Plasminogen Deficiency on the Contribution of Polymorphonuclear Leucocytes to Fibrin/ogenolysis
Plasminogen knock-out (PG/) mice provide an unique opportunity for the study of alternative mediators of fibrinolysis. Polymorpho-nuclear leucocytes (PMNs) contain non-plasmin fibrinolytic proteases, however the degree to which these cells contribute to fibrin(ogen) degradation in these animals is not known. Thrombi were generated in carotid arteries and jugular veins of PG/ and wild type (PG+/+) mice following adventitial application of a 20% ferric chloride solution. PMNs, identified histologically on H&E staining and by immunohistochemistry using anti-mouse PMN RB6-8C5 antibody, accumulated within the thrombus by 6 h after the injury and peaked at 24 h. There was significantly greater retention of PMNs within the thrombi of PG/ mice from 48 to 72 h than in the PG+/+ controls (at 72 h: PG/255 41 cell/mm2 (n = 5), PG+/+ 61 10 cell/mm2 (n = 5), p<0.01 in the arterial thrombi; PG/ 252 50 cell/mm2 (n = 5), PG+/+ 100 36 cell/mm2 (n = 5), p<0.05 in the venous thrombi), providing potential for more PMN derived fibrinolytic enzymes to be present at late times after a thrombotic challengeh in PG/ mice relative to the PG+/+ controls. Intact PMNs were elicited from the peritoneal cavities of PG/ and PG+/+ mice following 4% thioglycolate stimulation. In vitro studies showed PMNs from PG/ mice to release greater quantities of 10% trichloroacetic acid (TCA)-soluble fibrinopeptides from I125-labeled fibrinogen, than cells from PG+/+ controls although these differences did not become apparent until after 24 h of incubation (at 72 h incubation: PG/ 918 n/10 106 cells/0.5 ml, PG+/+ 589 ng/10 106 cells/0.5 ml p = 0.005). Furthermore, autoradiographic analysis of the I125-labeled fibrinogen degradation products showed the cleavage pattern by PG/ PMNs to be distinct from that produced by PG+/+ PMNs. These data suggest that a relatively greater role for PMNs-initiated fibrinolysis exists in the setting of plasminogen deficiency, although this prominence only becomes evident more than 24 h after the thrombotic insult. In addition, mechanisms responsible for the process in PG/ mice may be distinct from those primarily responsible for the process in PMNs from PG+/+ mice.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 88, 11/2002
Pages: 805 - 810