Download PDF
Thromb Haemost 1996; 75(01): 118-126
DOI: 10.1055/s-0038-1650231
Original Article
Schattauer GmbH Stuttgart

Anti-thrombotic Effect of a PAI-1 Inhibitor in Rats Given Endotoxin

T Abrahamsson
1   The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
,
V Nerme
1   The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
,
M Strömqvist
1   The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
,
B Åkerblom
1   The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
,
A Legnehed
1   The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
,
K Pettersson
1   The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
,
A Westin Eriksson
1   The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
› Author Affiliations
Further Information

Publication History

Received 23 February 1995

Accepted after resubmission 28 September 1995

Publication Date:
10 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

The aim of this study was to investigate the anti-thrombotic effects of an inhibitor of the plasminogen activator inhibitor-1 (PAI-1) in rats given endotoxin. In studies in vitro, PRAP-1, a Fab-fragment of a polyclonal antibody against human PAI-1, was shown to inhibit PAI-1 activity in rat plasma as well as to stimulate clot-lysis of the euglobulin fraction derived from rat plasma. Endotoxin administered to anaesthetised rats produced a marked increase in plasma PAI-1 activity. To study fibrin formation and lysis in vivo after intravenous (i. v.) injection of the coagulant enzyme batroxobin, 125I-fibrinogen was administered to the animals. The thrombi formed by batroxobin were rapidly lysed in control animals, while the rate of lysis was markedly attenuated in rats given endotoxin. PRAP-1 was administered i.v. (bolus + infusion) to rats given endotoxin and batroxobin and the PAI-1 inhibitor caused a dose-dependent decrease in the 125I-fibrin deposition in the lungs. An immunohistochemical technique was used to confirm this decrease in density of fibrin clots in the tissue. Furthermore, PRAP-1 decreased plasma PAI-1 activity in the rats and this reduction was correlated to the decrease in lung 125I-fibrin deposition at the corresponding time point. It is concluded that in this experimental model the PAI-1 antibody PRAP-1 may indeed inhibit thrombosis in animals exposed to endotoxin.

 

  • References

  • 1 Kruithof EKO. Plasminogen activator inhibitor type 1: Biochemical, biological and clinical aspects. Fibrinolysis 1988; 2 (suppl) (Suppl. 02) 59-70
    PubMedGoogle Scholar
  • 2 Wiman B, Hamsten A. The fibrinolytic enzyme system and its role in the etiology of thromboembolic disease. Semin Thromb Hemost 1990; 16: 207-216
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Aznar J, Estellés J. Roles of plasminogen activator inhibitor type 1 in the pathogenesis of coronary artery diseases. Haemostasis 1994; 24: 243-251
    PubMedGoogle Scholar
  • 4 Rocha E, Páramo JA. The relationship between impaired fibrinolysis and coronary heart disease: a role for PAI-1. Fibrinolysis 1994; 8: 294-303
    PubMedGoogle Scholar
  • 5 Krishnamurti C, Barr CF, Hassett MA, Young GD, Alving BM. Plasminogen activator inhibitor: a regulator of ancrod-induced fibrin deposition in rabbits. Blood 1987; 69: 798-803
    PubMedGoogle Scholar
  • 6 Reilly CF, Fujita T, Mayer EF, Siegfried ME. Both circulating and clot-bound plasminogen activator inhibitor-1 inhibit endogenous fibrinolysis in the rat. Arterioscler Thromb 1991; 11: 1276-1286
    CrossrefPubMedGoogle Scholar
  • 7 Carmeliet P, Stassen JM, Schoonjans L, Ream B, van de Oord JJ, De Mol M, Mulligan RC, Collen D. Plasminogen activator inhibitor-1 genedeficient mice. J Clin Invest 1993; 92: 2756-2760
    CrossrefPubMedGoogle Scholar
  • 8 Levi M, Biemond BJ, van Zonnenveld AJ, ten Cate JW, Pannekoek H. Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis. Circulation 1992; 85: 305-312
    CrossrefPubMedGoogle Scholar
  • 9 Biemond BJ, Levi M, Coronel R, Janse MJ, ten Cate JW, Pannekoek H. Thrombolysis and reocclusion in experimental jugular vein and coronary artery thrombosis: effects of a plasminogen activator inhibitor type 1 neutralizing monoclonal antibody. Circulation 1995; 91: 1175-1181
    CrossrefPubMedGoogle Scholar
  • 10 Emeis JJ, Kooistra T. Interleukin and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. J Exp Med 1986; 163: 1260-1266
    CrossrefPubMedGoogle Scholar
  • 11 Suffredini A, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 1989; 320: 1165-1172
    CrossrefPubMedGoogle Scholar
  • 12 Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Büler HR, van Deventer SJH, Hack CE, ten Cate JW, Rosenberg RD. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994; 93: 114-120
    CrossrefPubMedGoogle Scholar
  • 13 Pádro T, Quax PHA, van den Hoogen CM, Roholl P, Verheijen JH, Emeis JJ. Tissue-type plasminogen activator and its inhibitor in rat aorta. Arterioscler Thromb 1994; 14: 1459-1465
    CrossrefPubMedGoogle Scholar
  • 15 Pirkle H, Stocker K. Thrombin-like enzymes from snake venoms: An inventory. Thromb Haemost 1991; 65: 444-450
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Kwaan HC, Barlow GH. The mechanisms of action of arvin and reptilase. Thrombos Diathes Haemorrh 1971; 47 (suppl) (Suppl. 01) 361-369
    PubMedGoogle Scholar
  • 17 Pizzo SV, Schwartz ML, Hill RL, McKee PA. Mechanism of ancrod anticoagulation. A direct proteolytic effect on fibrin. J Clin Invest 1972; 51: 2841-2850
    CrossrefPubMedGoogle Scholar
  • 18 Regoeczi E, Gergely J, McFarlane AS. In vivo effects of Agkistrodon rhodostoma venom: Studies with fibrinogen-131I. J Clin Invest 1966; 45: 1202-1212
    CrossrefPubMedGoogle Scholar
  • 19 Klöcking HP, Markwardt F, Güttner J. On the mechanism of batroxobin-induced fibrinolysis. Pharmazie 1989; 44: 504-505
    PubMedGoogle Scholar
  • 20 Strömqvist M, Andersson J-O, Boström S, Deinum J, Ehnebom J, Enquist K, Johansson T, Hansson L. Separation of active and inactive forms of recombinant human plasminogen activator inhibitor typel (PAI-1) expressed in Chinese hamster ovary cells: Comparison with native human PAI-1. Protein Express Purif 1994; 5: 309-316
    CrossrefPubMedGoogle Scholar
  • 21 Gallimore MJ, Tyler HM, Shaw JTB. The measurement of fibrinolysis in the rat. Thrombos Diathes Haemorrh 1971; 26: 295-310
    PubMedGoogle Scholar
  • 22 Chmielewska J, Ránby M, Wiman B. Evidence for a rapid inhibitor to tissue plasminogen activator in plasma. Thromb Res 1983; 31: 427-436
    CrossrefPubMedGoogle Scholar
  • 23 Axenborg J, Hirsch I. A PC-based on-line system for physiological in vivo and in vitro experiments. Comp Methods Progr Biomed 1993; 41: 55-67
    CrossrefPubMedGoogle Scholar
  • 24 Longstaff C. Studies on the mechanism of action of aprotinin and tranex-amic acid as plasmin inhibitors and antifibrinolytic agents. Blood Coag Fibrinol 1994; 5: 537-542
    PubMedGoogle Scholar
  • 25 Regoeczi E, Brain MC. Organ distribution of fibrin in disseminated intra-vascular coagulation. Brit J Haemat 1969; 17: 73-81
    CrossrefPubMedGoogle Scholar
  • 26 Lenfors S, Marberg L, Wikström S, Jonsson U, Westin-Eriksson A, Gustafsson D. A new rat model of arterial thrombosis with a platelet-rich head and an erythrocyte-rich tail: thrombolysis experiments with specific thrombin inhibition. Blood Coag Fibrinol 1993; 4: 263-271
    CrossrefPubMedGoogle Scholar
  • 27 Green CJ. Animal anaesthesia. Laboratory animals Ltd; London: 1979
    Google Scholar
  • 28 Schneider DJ, Nordt TK, Sobel BE. Attenuated fibrinolysis and accelerated atherogenesis in type II diabetic patients. Diabetes 1993; 42: 1-7
    CrossrefPubMedGoogle Scholar
  • 29 Juhan-Vague I, Alessi MC. Plasminogen activator inhibitor-1 and athero-thrombosis. Thromb Haemost 1993; 70: 138-143
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Eriksson BI, Eriksson E, Gyzander E, Teger-Nilsson A-C, Risberg B. Thrombosis after hip replacement. Relationship to the fibrinolytic system. Acta Orthop Scand 1989; 60: 159-163
    CrossrefPubMedGoogle Scholar
  • 31 Eriksson BI, Eriksson E, Risberg B. Impaired fibrinolysis and postoperative thrombo-embolism in orthopedic patients. Thromb Res 1991; 1-2 55-64
    PubMedGoogle Scholar
  • 32 Hamsten A, Wiman B, de Faire U, Blombæck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563
    CrossrefPubMedGoogle Scholar
  • 33 Masuda T, Yasue H, Ogawa H, Misumi I, Sakamoto T, Okubo H, Miyao Y, Kato H. Plasma plasminogen activator inhibitor activity and tissue plasminogen activator levels in patients with unstable angina and those with coronary spastic angina. Am Heart J 1992; 124: 314-319
    CrossrefPubMedGoogle Scholar
  • 34 Ihnken K, Speiser W, Ruf W, Thiel W, Schlepper M, Müller-Berghaus G. High PAI activity with correlation to triglyceride and HDL cholesterol values in patients with coronary artery disease with no difference in survivors of myocardial infarction. Ann Hematol 1993; 67: 237-244
    CrossrefPubMedGoogle Scholar
  • 35 Schneiderman J, Sawdey MS, Keeton MR, Bordin GM, Bernstein EF, Dilley RB, Loskutoff DJ. Increased type 1 plasminogen activator inhibitor gene expression in athersclerotic human arteries. Proc Natl Acad Sci 1992; 89: 6998-7002
    CrossrefPubMedGoogle Scholar
  • 36 Stringer HAR, van Swieten P, Heijnen HFG, Sixma JJ, Pannekoek H. Plasminogen activator inhibitor-1 released from activated platelets plays a key role in thrombolysis resistance. Arterioscler Thromb 1994; 14: 1452-1458
    CrossrefPubMedGoogle Scholar
  • 37 Moore KL, Andreoli SP, Esmon NL, Esmon CT, Bang NU. Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest 1987; 79: 124-130
    CrossrefPubMedGoogle Scholar
  • 38 Pralong G, Calandra T, Glauser MP, Schellekens J, Verhoef J, Bachmann F, Kruithof EKO. Plasminogen activator inhibitor 1: A new prognostic marker in septic shock. Thromb Haemost 1989; 61: 459-462
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Colucci M, Paramo JA, Stassen JM, Collen D. Influence of the fast-acting inhibitor of plasminogen activator on in vivo thrombolysis induced by tissue-type plasminogen activator in rabbits. Interference of tissue-derived components. J Clin Invest 1986; 78: 138-144
    CrossrefPubMedGoogle Scholar
  • 40 Krishnamurti C, Young GD, Barr CF, Colleton CA, Alving BM. Enhancement of tissue plasminogen activator-induced fibrinolysis by activated protein C in endotoxin-treated rabbits. J Lab Clin Med 1991; 118: 523-530
    PubMedGoogle Scholar
  • 41 Saldeen T. Quantitative determination of intravascular coagulation in the lungs of experimental animals. Scand J Haemat 1969; 6: 205-215
    PubMedGoogle Scholar