Download PDF
Thromb Haemost 1992; 68(02): 180-184
DOI: 10.1055/s-0038-1656345
Original Article
Schattauer GmbH Stuttgart

Depression of Tissue-Type Plasminogen Activator and Enhancement of Urokinase-Type Plasminogen Activator as an Expression of Local Inflammation

Emile J P Brommer
The Gaubius Laboratory IVVO-TNO, University Hospital, Leiden, The Netherlands
,
Gerard Dooijewaard
The Gaubius Laboratory IVVO-TNO, University Hospital, Leiden, The Netherlands
,
Ben A C Dijkmans
*   The Dept. of Rheumatology, University Hospital, Leiden, The Netherlands
,
Ferdinand C Breedveld
*   The Dept. of Rheumatology, University Hospital, Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 22 October 1991

Accepted after revision 02 March 1992

Publication Date:
03 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Inflammatory processes are accompanied by extravascular deposition and breakdown of fibrin. We measured fibrinolytic parameters in synovial fluid (SF) and in plasma of 36 patients with rheumatoid arthritis (RA). As a control, SF of 13 patients with blunt knee trauma, and plasma of 17 healthy volunteers were studied. In RA patients, extravascular t-PA mediated plasminogen activation was depressed: mean SF tissue-type plasminogen activator (t-PA:Ag) concentration (2.1 ± 1.6 ng/ml) was four-fold lower, and plasminogen activator inhibitor (PAI) activity (284 ± 212%) four-fold higher than the plasma values of the same patients or of healthy donors. In contrast, u-PA related plasminogen activation was strongly enhanced: urokinase-type plasminogen activator (u-PA) antigen (23.1 ±12.4 ng/ml) was more than four-fold higher, single-chain u-PA (scu-PA) (5.3 ± 1.9 ng/ml) three-fold higher than in plasma of the same patients or of healthy donors, and active two-chain u-PA (tcu-PA) was detected in 14 of the 36 SF samples of RA patients. All of these changes in extravascular fibrinolytic parameters correspond with those induced by inflammatory mediators in cell cultures. In joint effusions of patients with a blunt knee trauma, the effects were intermediate: u-PA related parameters showed moderate changes in the same direction as in arthritis; t-PA antigen was also decreased. The only exception was that PAI was not increased. We conclude that the findings in traumatic effusions reflect transient effects as a reaction to trauma. In joint inflammation, the depressed t-PA mediated plasminogen activation, although more than compensated by the enhanced u-PA mediated plasminogen activation, results in protraction of fibrin removal. Besides, the enhanced u-PA activation might lead to proteolytic damage of the cartilage.

 

  • References

  • 1 Albrechtsen O, Astrup T. Fibrinolytic activity in the organism. Acta Phys Scand 1959; 47 (Suppl 165) 83-90
    CrossrefPubMedGoogle Scholar
  • 2 Astrup T, Sjølin KE. Thromboplastic and fibrinolytic activity of human synovial membrane and fibrous capsular tissue. Proc Soc Exp Biol Med 1958; 97: 852-853
    CrossrefPubMedGoogle Scholar
  • 3 Tympanidis K, Astrup T. Fibrinolytic activity in injured rat skin. Exp Mol Pathol 1972; 16: 101-108
    CrossrefPubMedGoogle Scholar
  • 4 Huber K, Wojta J, Kirchheimer JC, Ermler D, Binder BR. Plasminogen activators and plasminogen activator inhibitor in malignant and non-malignant ascitic fluid. Eur J Clin Invest 1988; 18: 595-599
    CrossrefPubMedGoogle Scholar
  • 5 Wilhelm O, Hafter R, Graeff H. Fibrinolysis in ascitic fluid: isolation and characterization of fibrin derivatives, their interaction with albumin. Thromb Res 1987; 47: 673-681
    CrossrefPubMedGoogle Scholar
  • 6 Agrenius V, Chmielewska J, Widström O, Blombäck M. Pleural fibrinolytic activity is decreased in inflammation as demonstrated in quinacrine pleurodesis treatment of malignant pleural effusion. Am Rev Respir Dis 1989; 140: 1381-1385
    CrossrefPubMedGoogle Scholar
  • 7 Jespersen J, Brommer EJP, Haverkate F, Nieuwenhuizen W. Degradation products of fibrin and of fibrinogen in synovial fluid and in plasma of patients with rheumatoid arthritis. Fibrinolysis 1989; 3: 183-186
    PubMedGoogle Scholar
  • 8 Sprengers E, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387
    PubMedGoogle Scholar
  • 9 Bernik MB, Oller EP. Regulation of fibrinolysis through activation and inhibition of activation of a plasminogen proactivator (preurokinase). Thromb Haemostas 1977; 38: 136
    PubMedGoogle Scholar
  • 10 Gurewich V, Pannell R, Louie S, Kelley P, Suddith RL, Greenlee R. Effective and fibrin-specific clot lysis by a zymogen precursor from urokinase (pro-urokinase). J Clin Invest 1984; 73: 1731-1739
    CrossrefPubMedGoogle Scholar
  • 11 Pannell R, Gurewich V. Pro-urokinase: a study of its stability in plasma and of a mechanism for its selective fibrinolytic effect. Blood 1986; 67: 1215-1223
    PubMedGoogle Scholar
  • 12 Lijnen HR, Van Hoef B, De Cock F, Collen D. The mechanism of plasminogen activation and fibrin dissolution by single-chain urokinase-type plasminogen activator in a plasma milieu in vitro. Blood 1989; 73: 1864-1872
    PubMedGoogle Scholar
  • 13 Blasi F, Vassalli J-D, Danø K. Urokinase-type plasminogen activator: proenzyme, receptor, and inhibitors. J Cell Biol 1987; 104: 801-804
    CrossrefPubMedGoogle Scholar
  • 14 Cubellis MV, Wun TC, Blasi F. Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. EMBO J 1990; 9: 1079-1085
    PubMedGoogle Scholar
  • 15 Binnema D, Van Iersel JJL, Dooijewaard G. Quantitation of urokinase antigen in plasma and culture media by use of an ELISA. Thromb Res 1986; 43: 569-577
    CrossrefPubMedGoogle Scholar
  • 16 Van der Poll T, Levi M, Büller HR, van Deventer SJH, de Boer JP, Hack CE, ten Cate JW. Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 1991; 174: 729-732
    CrossrefPubMedGoogle Scholar
  • 17 Van Deventer SJH, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76: 2520-2526
    PubMedGoogle Scholar
  • 18 Philippé J, Offner F, Declerck PJ, Leroux-Roels G, Vogelaers D, Baele G, Collen D. Fibrinolysis and coagulation in patients with infectious disease and sepsis. Thromb Haemostas 1991; 65: 291-295
    PubMedGoogle Scholar
  • 19 Van Hinsbergh VWM, Van den Berg EA, Fiers W, Dooijewaard G. Tumor necrosis factor induces the production of urokinase-type plasminogen activator by human endothelial cells. Blood 1990; 75: 1991-1998
    PubMedGoogle Scholar
  • 20 Bevilacqua MP, Schleef RR, Gimbrone MA, Loskutoff DJ. Regulation of the fibrinolytic system of cultured human vascular endothelium by interleukin 1. J Clin Invest 1986; 78: 587-591
    CrossrefPubMedGoogle Scholar
  • 21 Schleef RR, Bevilacqua MP, Sawdey M, Gimbrone MA, Loskutoff DJ. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen and type 1 plasminogen activator inhibitor. J Biol Chem 1988; 263: 5797-803
    PubMedGoogle Scholar
  • 22 Van Hinsbergh VWM, Kooistra T, Scheffer MA, Van Bockel JH, Van Muijen GNP. Characterization and fibrinolytic properties of human omental tissue mesothelial cells. Comparison with endothelial cells. Blood 1990; 75: 1490-1497
    PubMedGoogle Scholar
  • 23 American Rheumatism Association on criteria for rheumatoid arthritis: Primer on the rheumatic diseases. JAMA 1959 171. 1213
    PubMedGoogle Scholar
  • 24 Verheijen JH, Chang GTG, Kluft C. Evidence for the occurrence of a fast-acting inhibitor of tissue-type plasminogen activator in human plasma. Thromb Haemostas 1984; 51: 392-395
    PubMedGoogle Scholar
  • 25 Doornbos R, Prins HJ. On slippage tests. Indag Math 1958; 20 38-55 and 20 438-447
    PubMedGoogle Scholar
  • 26 Wood DD, Ihrie EJ, Dinarello CA, Cohen PL. Isolation of an interleukin-1-like factor from human joint effusions. Arthritis Rheum 1983; 26: 975-983
    CrossrefPubMedGoogle Scholar
  • 27 Miossec P, Dinarello CA, Ziff M. Interleukin-1 lymphocyte chemotactic activity in rheumatoid arthritis synovial fluid. Arthritis Rheum 1986; 29: 461-470
    CrossrefPubMedGoogle Scholar
  • 28 Houssiau FA, Devogelaer JP, Van Damme J, Nagant de Deuxchaisnes C, Van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 1988; 31: 784-788
    CrossrefPubMedGoogle Scholar
  • 29 Di Giovine FS, Nuki G, Duff W. Tumour necrosis factor in synovial exsudates. Ann Rheum Dis 1988; 47: 768-772
    CrossrefPubMedGoogle Scholar
  • 30 Mochan E, Uhl J. Elevations in synovial fluid plasminogen activator in patients with rheumatoid arthritis. J Rheumatol 1984; 11: 123-128
    PubMedGoogle Scholar
  • 31 Inman RD, Harpel PC. α2-Plasmin inhibitor-plasmin complexes in synovial fluid. J Rheumatol 1986; 13: 535-537
    PubMedGoogle Scholar
  • 32 Kikuchi H, Tanaka S, Matsuo O. Plasminogen activator in synovial fluid from patients with rheumatoid arthritis. J Rheumatol 1987; 14: 439-445
    PubMedGoogle Scholar
  • 33 Lindenhayn K, Heilmann HH, Regling G, Haupt R. Plasminogen-activator-Aktivität der Synovialflüssigkeit als Indikator für Aktivierungsphänomene bei degenerativen Gelenkerkrankungen. Z Rheumatol 1989; 48: 246-253
    PubMedGoogle Scholar
  • 34 Medcalf RL, Hamilton JA. Human synovial fibroblasts produce urokinase-type plasminogen activator. Arthritis Rheum 1986; 29: 1397-401
    CrossrefPubMedGoogle Scholar
  • 35 Vitti G, Hamilton JA. Modulation of urokinase-type plasminogen activator messenger RNA levels in human synovial fibroblasts by interleukin-1, retinoic acid, and glucocorticoid. Arthritis Rheum 1988; 31: 1046-1051
    CrossrefPubMedGoogle Scholar
  • 36 Leizer T, Clarris BJ, Ash PE, Saklatvala J, Hamilton JA. Interleukin-1β and interleukin-1α stimulate the plasminogen activator activity and prostaglandin E2 levels of human synovial cells. Arthritis Rheum 1987; 30: 562-566
    CrossrefPubMedGoogle Scholar
  • 37 Saksela O, Hovi T, Vaheri A. Urokinase-type plasminogen activator and its inhibitor secreted by cultured human monocyte-macrophages. J Cell Physiol 1985; 122: 125-132
    CrossrefPubMedGoogle Scholar
  • 38 Vassali J-D, Dayer J-M, Wohlwend A, Belin D. Concomitant secretion of prourokinase and of a plasminogen activator-specific inhibitor by cultured human monocytes-macrophages. J Exp Med 1984; 159: 1653-1668
    CrossrefPubMedGoogle Scholar
  • 39 Grau E, Moroz LA. Fibrinolytic activity of normal human blood monocytes. Thromb Res 1989; 53: 145-162
    CrossrefPubMedGoogle Scholar
  • 40 Hamaguchi M, Morishita Y, Takahashi I, Ogura M, Takamatsu J, Saito H. FDP D-dimer induces the secretion of interleukin-1, urokinase-type plasminogen activator, and plasminogen activator inhibitor-2 in a human promonocytic leukemia cell line. Blood 1991; 77: 94-100
    Google Scholar
  • 41 Hart PH, Vitti GF, Burgess DR, Whitty GA, Royston K, Hamilton JA. Activation of human monocytes by granulocyte-macrophage colony-stimulating factor: increased urokinase-type plasminogen activator activity. Blood 1991; 77: 841-848
    PubMedGoogle Scholar
  • 42 Weinberg JB, Pippen AMM, Greenberg CS. Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 1991; 34: 996-1005
    CrossrefPubMedGoogle Scholar
  • 43 Bunning RAD, Crawford A, Richardson HJ, Opdenakker G, Van Damme J, Russell RGG. Interleukin 1 preferentially stimulates the production of tissue-type plasminogen activator by human articular chondrocytes. Biochem Biophys Acta 1987; 924: 473-482
    CrossrefPubMedGoogle Scholar
  • 44 Del Rosso M, Fibbi G, Magnelli L, Pucci M, Dini G, Grappone C, Caldini R, Serni U, Colombo F, Borella F. Modulation of urokinase receptors on human synovial cells and osteoarthritis chondrocytes by diacetylrhein. Int J Tiss Reac 1990; 12: 91-100
    PubMedGoogle Scholar
  • 45 Gurewich V, Pannell R. Inactivation of single-chain urokinase (pro-urokinase) by thrombin and thrombin-like enzymes: relevance of the findings to the interpretation of fibrin-binding experiments. Blood 1987; 69: 769-772
    PubMedGoogle Scholar
  • 46 Schmitt M, Kanayama N, Henschen A, Hollrieder A, Hafter R, Gulba D, Jänicke F, Graeff H. Elastase released from human granulocytes stimulated with N-formyl-chemotactic peptide prevents activation of tumar cell prourokinase (pro-uPA). FEBS 1989; 255: 83-88
    CrossrefPubMedGoogle Scholar
  • 47 Matsuo O, Tanaka S, Kikuchi H. Effect of urinary trypsin inhibitor on osteoarthritis. Thromb Res 1988; 52: 237-245
    CrossrefPubMedGoogle Scholar
  • 48 Grøndahl-Hansen J, Kirkeby LT, Ralfkiaer E, Kristensen P, Lund LR, Danø K. Urokinase-type plasminogen activator in endothelial cells during acute inflammation of the appendix. Am J Pathol 1989; 135: 631-636
    PubMedGoogle Scholar
  • 49 Elliott R, Stephens RW, Doe WF. Expression of urokinase-type plasminogen activator in the mucosal lesions of inflammatory bowel disease. J Gastreneterol Hepatol 1987; 2: 517-523
    PubMedGoogle Scholar
  • 50 De Bruin PAF, Crama-Bohbouth G, Verspaghet HW, Verheijen JH, Dooijewaard G, Weterman IT, Lamers CBHW. Plasminogen activators in the intestine of patients with inflammatory bowel disease. Thromb Haemostas 1988; 60: 262-266
    PubMedGoogle Scholar
  • 51 Brommer EJP, Verheijen JH, Chang GTG, Rijken DC. Masking of fibrinolytic response to stimulation by an inhibitor of tissue-type plasminogen activator in plasma. Thromb Haemostas 1984; 52: 154-156
    PubMedGoogle Scholar
  • 52 Ossowski L, Quigley JP, Kellerman GM, Reich E. Fibrinolysis associated with oncogenic transformation. Requirement of plasminogen for correlated changes in cellular morphology, colony formation an agar, and migration. J Exp Med 1973; 138: 1056-1054
    PubMedGoogle Scholar
  • 53 Estreicher A, Muhlhauser J, Carpentier JL, Orci L, Vassalli JD. The receptor urokinase-type plasminogen activator polarizes expression of the protease to the leading egde of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol 1990; 111: 783-792
    CrossrefPubMedGoogle Scholar
  • 54 Danø K, Andreason PA, Grøndahl-Hansen J, Kristensen P, Nielsen LS, Skriver L. Plasminogen activators, tissue degradation and cancer. Adv Cancer Res 1985; 44: 139-266
    PubMedGoogle Scholar
  • 55 Kirchheimer JC, Wojta J, Heinert G, Christ G, Heger ME, Pflüger H, Binder BR. Effect of urokinase on the proliferation of primary cultures of human prostatic cells. Thromb Res 1987; 48: 291-298
    CrossrefPubMedGoogle Scholar
  • 56 Werb Z, Mainardi CL, Vater CA, Harris ED. Endogenous activation of latent collagenase by rheumatoid synovial cells. N Engl J Med 1977; 296: 1017-1023
    CrossrefPubMedGoogle Scholar
  • 57 Liotta L, Goldfarb R, Brundage R, Siegal G, Terranova V, Garbisa S. Effect of plasminogen activator (urokinase), plasmin, and thrombin on glycoprotein and collagenous components of basement membrane. Cancer Res 1981; 41: 4629-4636
    PubMedGoogle Scholar
  • 58 Collen D, Stassen JM, Stump DC, Verstraete M. Synergism of thrombolytic agents in vivo. Circulation 1986; 4: 838-842
    PubMedGoogle Scholar
  • 59 Gurewich V. The sequential, complementary and synergistic activation of fibrin-bound plasminogen by tissue plasminogen activator and prourokinase. Fibrinolysis 1989; 3: 59-66
    PubMedGoogle Scholar
  • 60 Lohmander LS, Dahlberg L, Ryd L, Heinegård D. Increased levels of proteoglycan fragments in knee joint fluid after trauma. Arthritis Rheum 1989; 32: 1434-1439
    CrossrefPubMedGoogle Scholar