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Thromb Haemost 2000; 84(01): 65-70
DOI: 10.1055/s-0037-1613969
Commentary
Schattauer GmbH

Prevention of Renal Fibrin Deposition in Endotoxin-induced DIC through Inhibition of PAI-1

Ramón Montes
1   From the Hemostasis and Thrombosis Research Unit, School of Medicine, University of Navarra, Pamplona, Spain
,
Paul J. Declerck
2   Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Belgium, Pamplona, Spain
,
Alfonso Calvo
3   Histology Department, University of Navarra, Pamplona, Spain
,
Marta Montes
4   Pathology Service, Hospital Virgen del Camino, Pamplona, Spain
,
José Hermida
1   From the Hemostasis and Thrombosis Research Unit, School of Medicine, University of Navarra, Pamplona, Spain
,
María C. Muñoz
1   From the Hemostasis and Thrombosis Research Unit, School of Medicine, University of Navarra, Pamplona, Spain
,
Eduardo Rocha
1   From the Hemostasis and Thrombosis Research Unit, School of Medicine, University of Navarra, Pamplona, Spain
5   Hematology Service, University Clinic of Navarra, Pamplona, Spain
› Author AffiliationsThis work was supported in part by grant PM94-1553 from the DGICYT of the Ministerio de Educación y Ciencia, Spain. This work was supported in part by a grant from the Fund for Scientific Research (F. W. O. – Vlaanderen, project 7.0034.98). We acknowledge the technical assistance of Mercedes Fernández and Yolanda Azcona.
Further Information

Publication History

Received 14 October 1999

Accepted after resubmission 21 February 2000

Publication Date:
10 December 2017 (online)

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Summary

Plasminogen activator inhibitor-1 (PAI-1) increases in endotoxemia thus possibly cooperating in altering the hemostatic balance in a prothrombotic direction. The effect of the inhibition of PAI-1 with the monoclonal antibody MA-33B8 was studied systemically and in kidneys in a lapine model of endotoxin-induced disseminated intravascular coagulation (DIC). The increase in plasmatic PAI activity in the control group (n = 9) was inhibited in the MA-33B8 treated rabbits (n = 5). Control rabbits showed renal fibrin deposits, whereas only one of the MA-33B8 rabbits did so. These results were confirmed immunohistochemically in kidneys as PAI-1 immunostaining was seen inside the glomeruli and larger vessels in the control group, whereas MA-33B8 rabbits showed a remarkable decrease, demonstrating that MA-33B8 successfully inhibited PAI-1 in the kidneys as well. Therefore evidence for the important role of PAI-1 in fibrin generation in endotoxin-induced DIC is presented, suggesting that strategies aiming at its reduction can be useful in this pathology.

Key words

PAI-1 - sepsis - endotoxemia - monoclonal antibodies - kidney
 

  • References

  • 1 Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 1982; 257: 2912-9.
    PubMedSearch in Google Scholar
  • 2 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-7.
    PubMedSearch in Google Scholar
  • 3 Wiman B, Hamsten A. Impaired fibrinolysis and risk of thromboembolism. Prog Cardiovasc Dis 1991; 34: 179-92.
    CrossrefPubMedSearch in Google Scholar
  • 4 Dawson S, Henney A. The status of PAI-1 as a risk factor for arterial and thrombotic disease: a review. Atherosclerosis 1992; 95: 105-17.
    CrossrefPubMedSearch in Google Scholar
  • 5 Levi M, Biemond BJ, van Zonneveld A-J, 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: 305-12.
    CrossrefPubMedSearch in Google Scholar
  • 6 Biemond BJ, Levi M, Coronel R, Janse MJ, ten Cate JW, Pannekoek H. Thrombolysis and reocclusion in experimental jugular vein and coronary artery thrombosis. Circulation 1995; 91: 1175-81.
    CrossrefPubMedSearch in Google Scholar
  • 7 Berry CN, Lunven C, Lechaire I, Girardot C, O’Connor SE. Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis. Br J Pharmacol 1998; 125: 29-34.
    CrossrefPubMedSearch in Google Scholar
  • 8 Van Giezen JJJ, Wahlund G, Nerme V, Abrahamsson T. The Fab-fragment of a PAI-1 inhibiting antibody reduces thrombus size and restores blood flow in a rat model of arterial thrombosis. Thromb Haemost 1997; 77: 964-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Abrahamsson T, Nerme V, Strömqvist M, Åkerblom B, Legnehed A, Pettersson K, Westin-Eriksson A. Anti-thrombotic effect of a PAI-1 inhibitor in rats given endotoxin. Thromb Haemost 1996; 75: 118-26.
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Colucci M, Páramo JA, Collen D. Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation. J Clin Invest 1985; 75: 818-24.
    CrossrefPubMedSearch in Google Scholar
  • 11 Gómez C, Páramo JA, Colucci M, Rocha E. Effect of heparin and/or antithrombin III on the generation of endotoxin-induced plasminogen activator inhibitor. Thromb Haemost 1989; 62: 694-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Paloma MJ, Páramo JA, Rocha E. Effect of DDAVP on endotoxin-induced intravascular coagulation in rabbits. Thromb Haemost 1992; 68: 306-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Paloma MJ, Páramo JA, Rocha E. Endotoxin-induced intravascular coagulation in rabbits: Effect of tissue plasminogen activator vs urokinase on PAI generation, fibrin deposits and mortality. Thromb Haemost 1995; 74: 1578-82.
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Hermida J, Montes R, Páramo JA, Rocha E. Endotoxin-induced disseminated intravascular coagulation in rabbits: effect of recombinant hirudin on hemostatic parameters, fibrin deposits and mortality. J Lab Clin Med 1998; 131: 77-83.
    CrossrefPubMedSearch in Google Scholar
  • 15 Hermida J, Montes R, Muñoz MC, Orbe J, Páramo JA, Rocha E. Effects of low molecular weight heparin, alone or combined with antithrombin III, on mortality, fibrin deposits and hemostatic parameters in endotoxin-induced disseminated intravascular coagulation in rabbits. Am J Hematol 1999; 60: 6-11.
    CrossrefPubMedSearch in Google Scholar
  • 16 Muñoz MC, Montes R, Hermida J, Orbe J, Páramo JA, Rocha E. Effect of the administration of recombinant hirudin and/or t-PA on endotoxininduced disseminated intravascular coagulation model in rabbits. Br J Haematol 1999; 105: 117-22.
    CrossrefPubMedSearch in Google Scholar
  • 17 Debrock S, Declerck PJ. Neutralization of plasminogen activator inhibitor-1 inhibitory properties: identification of two different mechanisms. Biochim Biophys Acta 1997; 1337: 257-66.
    CrossrefPubMedSearch in Google Scholar
  • 18 Vleugels N, Gils A, Mannaerts S, Knockaert I, Declerck PJ. Evaluation of the mechanism of inactivation of plasminogen activator inhibitor-1 by monoclonal antibodies using a stable variant. Fibrinolysis & Proteolysis 1998; 12: 277-82.
    CrossrefPubMedSearch in Google Scholar
  • 19 Verhamme I, Kvassman JO, Day D, Debrock S, Vleugels N, Declerck PJ, Shore JD. Accelerated conversion of human plasminogen activator inhibitor-1 to its latent form by antibody binding. J Biol Chem 1999; 274: 17511-7.
    CrossrefPubMedSearch in Google Scholar
  • 20 Keeton M, Eguchi Y, Sawdey M, Ahn C, Loskutoff DJ. Cellular localization of type 1 plasminogen activator inhibitor messenger RNA and protein in murine renal tissue. Am J Pathol 1993; 142: 59-70.
    PubMedSearch in Google Scholar
  • 21 Yamamoto K, Loskutoff DJ, Saito H. Renal expression of fibrinolytic genes and tissue factor in a murine model of renal disease as a function of age. Semin Thromb Hemost 1998; 24: 261-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256: 495-7.
    CrossrefPubMedSearch in Google Scholar
  • 23 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmug des Fibrinogens. Acta Haematol 1957; 17: 237.
    CrossrefPubMedSearch in Google Scholar
  • 24 Abilgaard U, Lie M, ØDegard OR. A simple amidolytic method for the determination of functionally active antithrombin III. Scand J Clin Lab Invest 1976; 36: 109-12.
    CrossrefPubMedSearch in Google Scholar
  • 25 Vinazzer H, Pangraz U. Protein C: comparison of different assays in normal and abnormal plasma samples. Thromb Res 1987; 46: 1-8.
    CrossrefPubMedSearch in Google Scholar
  • 26 Páramo JA, Alfaro MJ, Rocha E. Postoperative changes in the plasmatic levels of tissue-type plasminogen activator and its fast acting inhibitor. Relationship to deep vein thrombosis and influence of prophylaxis. Thromb Haemost 1985; 54: 713-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 27 Shu SY, Ju G, Fan LZ. The glucose-oxidase DAB nickel method in peroxidase histochemistry of the nervous system. Neurosci Lett 1988; 85: 169-71.
    CrossrefPubMedSearch in Google Scholar
  • 28 Ngo TH, Declerck PJ. Suppression of plasminogen activator inhibitor (PAI-1) activity levels in rats by monoclonal antibodies. Fibrinolysis 1998; 12: 335-9.
    PubMedSearch in Google Scholar
  • 29 Yamamoto K, Loskutoff DJ. The kidneys of mice with autoimmune disease acquire a hypofibrinolytic/procoagulant state that correlates with the development of glomerulonephritis and tissue microthrombosis. Am J Pathol 1997; 151: 725-34.
    PubMedSearch in Google Scholar
  • 30 Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. J Clin Invest 1991; 88: 1346-53.
    CrossrefPubMedSearch in Google Scholar
  • 31 Wang Y, Pratt JR, Hartley B, Evans B, Zhang L, Sacks SH. Expression of tissue type plasminogen activator and type 1 plasminogen activator inhibitor, and persistent fibrin deposition in chronic renal allograft failure. Kidney Int 1997; 52: 371-7.
    CrossrefPubMedSearch in Google Scholar
  • 32 Yamamoto K, Saito H. A pathological role of increased expression of plasminogen activator inhibitor-1 in human or animal disorders. Int J Hematol 1998; 68: 371-85.
    CrossrefPubMedSearch in Google Scholar
  • 33 Keeton M, Ahn C, Eguchi Y, Burlingame R, Loskutoff DJ. Expression of type 1 plasminogen activator inhibitor in renal tissue in murine lupus nephritis. Kidney Int 1995; 47: 148-57.
    CrossrefPubMedSearch in Google Scholar
  • 34 Duymelinck C, Dauwe SE, Nouwen EJ, De Broe ME, Verpooten GA. Cholesterol feeding accentuates the cyclosporine-induced elevation of renal plasminogen activator inhibitor type 1. Kidney Int 1997; 51: 1818-30.
    CrossrefPubMedSearch in Google Scholar
  • 35 Tang WH, Friess H, di Mola FF, Schilling M, Maurer C, Graber HU, Dervenis C, Zimmermann A, Buchler MW. Activation of the serine proteinase system in chronic kidney rejection. Transplantation 1998; 65: 1628-34.
    CrossrefPubMedSearch in Google Scholar
  • 36 Cole EH, Sweet J, Levy GA. Expression of macrophage procoagulant activity in murine systemic lupus erythematosus. J Clin Invest 1986; 78: 887-93.
    CrossrefPubMedSearch in Google Scholar
  • 37 Boswell JM, Yui MA, Burt DW, Kelley VE. Increased tumor necrosis factor and IL-1b gene expression in the kidneys of mice with lupus nephritis. J Immunol 1988; 141: 3050-4.
    PubMedSearch in Google Scholar
  • 38 Mathison J, Wolfson E, Ulevitch R. Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 1988; 81: 1925-37.
    CrossrefPubMedSearch in Google Scholar
  • 39 Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: Mechanisms of endotoxin resistance. Science 1986; 232: 977-80.
    CrossrefPubMedSearch in Google Scholar
  • 40 Border WA, Noble NA. Cytokines in kidney disease: The role of transforming growth factor-beta. Am J Kidney Dis 1993; 22: 105-13.
    CrossrefPubMedSearch in Google Scholar
  • 41 Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA. Expression of transforming growth factor B is elevated in human and experimental diabetic nephropahty. Proc Natl Acad Sci USA 1993; 90: 1814-8.
    CrossrefPubMedSearch in Google Scholar
  • 42 Okuda S, Nakamura T, Yamamoto T, Ruoslahti E, Border WA. Dietary protein restriction rapidly reduces transforming growth factor beta 1 expression in experimental glomerulonephritis. Proc Natl Acad Sci USA 1991; 88: 9765-9.
    CrossrefPubMedSearch in Google Scholar
  • 43 Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1. Nature 1990; 346: 371-4.
    CrossrefPubMedSearch in Google Scholar
  • 44 Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, Ruoslathi E. Nature 1992; 360: 361-4.
    CrossrefPubMedSearch in Google Scholar
  • 45 Berrettini M, Schleef RR, España F, Loskutoff DJ, Griffin JH. Interaction of type 1 plasminogen activator inhibitor with the enzymes of the contact activation system. J Biol Chem 1989; 264: 11738-43.
    PubMedSearch in Google Scholar
  • 46 Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90: 3819-43.
    PubMedSearch in Google Scholar
  • 47 Mantovani A, Bussolino F, Dejana E. Cytokine regulation of endothelial cell function. FASEB J 1992; 06: 2591-9.
    CrossrefPubMedSearch in Google Scholar
  • 48 Giroir BP. Mediators of septic shock: New approaches for interrupting the endogenous inflammatory cascade. Crit Care Med 1993; 21: 780-9.
    CrossrefPubMedSearch in Google Scholar