Download PDF
Thromb Haemost 2002; 87(01): 22-31
DOI: 10.1055/s-0037-1612938
Review Article
Schattauer GmbH

Gene Targeting of Components of the Fibrinolytic System

Victoria A. Ploplis
1   W. M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
,
Francis J. Castellino
1   W. M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
› Author Affiliations
Further Information

Publication History

Received 29 May 2001

Accepted after resubmission 25 September 2001

Publication Date:
14 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

A number of in vitro and in vivo observations have implicated components of the fibrinolytic system in events associated with diverse physiological and pathophysiological processes, ranging from embryo implantation to cancer. Advances in gene targeting technology have led to the generation of mice deficient for components of the fibrinolytic system. Remarkably, these animals survive to adulthood with few spontaneous life threatening events. Thus, these mice are valuable resources for in vivo studies, not only for hemostasis-related research, but also for the relationships of these genes to other disease states associated with cellular growth and mobility, along with angiogenesis, vascular remodeling, inflammation, wound healing, and tumor growth and dissemination.

Keywords

Gene deficiencies - fibrinolysis - hemostasis - blood
 

  • References

  • 1 Carmeliet P, Stassen JM, Schoonjans L, Ream B, van den Oord J, De Mol M, Mulligan RC, Collen D. Plasminogen activator inhibitor-1 gene-deficient mice. J Clin Invest 1993; 92: 2756-60.
    CrossrefPubMedGoogle Scholar
  • 2 Vassali JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991; 88: 1067-72.
    CrossrefPubMedGoogle Scholar
  • 3 Lala PK, Graham CH. Mechanisms of trophoblast invasiveness and their control: the role of proteases and protease inhibitors. Cancer Metastasis Rev 1990; 09: 369-79.
    CrossrefPubMedGoogle Scholar
  • 4 Ohlsson M, Peng XR, Liu YX, Jia XC, Hsueh AJW, Ny T. Hormone regulation of tissue-type plasminogen activator gene expression and plasminogen activator-mediated proteolysis. Semin Thromb Haemost 1991; 17: 286-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, De Vos R, van den Oord JJ, Collen D, Mulligan RC. Physiological consequences of loss of plasminogen activator function in mice. Nature 1994; 368: 419-24.
    CrossrefPubMedGoogle Scholar
  • 6 Huarte J, Belin D, Vassalli JD. Plasminogen activator in mouse and rat oocytes: induction during meiotic maturation. Cell 1985; 43: 551-8.
    CrossrefPubMedGoogle Scholar
  • 7 Tsafriri A, Bicsak TA, Cajander SB, Ny T, Hsueh AJW. Suppression of ovulation rate by antibodies to tissue-type plasminogen activator and alpha 2-antiplasmin. Endocrinology 1989; 124: 415-21.
    CrossrefPubMedGoogle Scholar
  • 8 Huarte J, Belin D, Bosco D, Sappino AP, Vassalli JD. Plasminogen activator and mouse spermatozoa : urokinase synthesis in the male genital tract and binding of the enzyme to the sperm cell surface. J Cell Biol 1987; 104: 1281-9.
    CrossrefPubMedGoogle Scholar
  • 9 Sappino AP, Huarte J, Belin D, Vassalli JD. Plasminogen activators in tissue remodeling and invasion: mRNA localization in mouse ovaries and implanting embryos. J Cell Biol 1989; 109: 2471-9.
    CrossrefPubMedGoogle Scholar
  • 10 Denker HW. Implantation. The role of proteinases and blockage of implantation by proteinase inhibitors. Adv Anat Embryol Cell Biol 1977; 53: 3-123.
    PubMedGoogle Scholar
  • 11 Strickland S, Reich E, Sherman MI. Plasminogen activator in early embryogenesis: enzyme production by trophoblast and parietal endoderm. Cell 1976; 09: 231-40.
    CrossrefPubMedGoogle Scholar
  • 12 Canipari R, O’Connell ML, Meyer G, Strickland S. Mouse ovarian granulosa cells produce urokinase-type plasminogen activator, whereas the corresponding rat cells produce tissue-type plasminogen activator. J Cell Biol 1987; 105: 977-81.
    CrossrefPubMedGoogle Scholar
  • 13 Lijnen HR, Moons L, Beelen V, Carmeliet P, Collen D. Biological effects of combined inactivation of plasminogen activator and plasminogen activator inhibitor-1 gene function in mice. Thromb Haemost 1995; 74: 1126-31.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Ploplis VA, Carmeliet P, Vazirzadeh S, Van Vlaenderen I, Moons L, Plow EF, Collen D. Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 1995; 92: 2585-93.
    CrossrefPubMedGoogle Scholar
  • 15 Bugge TH, Flick MJ, Daugherty CC, Degen JL. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes Dev 1995; 09: 794-807.
    CrossrefPubMedGoogle Scholar
  • 16 Hoover-Plow J, Wang N, Ploplis V. Growth and behavioral development in plasminogen gene-targeted mice. Growth Dev Aging 1999; 63: 13-32.
    PubMedGoogle Scholar
  • 17 Drew AF, Kaufman AH, Kombrinck KW, Danton MJ, Daugherty CC, Degen JL, Bugge TH. Ligneous conjunctivitis in plasminogen-deficient mice. Blood 1998; 91: 1616-24.
    PubMedGoogle Scholar
  • 18 Mingers AM, Philapitsch A, Zeitler P, Scuster V, Schwarz HP, Kreith HW. Human homozygous type I plasminogen deficiency and ligneous conjunctivitis. APMIS 1999; 107: 62-72.
    CrossrefPubMedGoogle Scholar
  • 19 Kraft J, Lieb W, Zeitler P, Scuster V. Ligneous conjunctivitis in a girl with severe type I plasminogen deficiency. Graefeís Arch Clin Exp Ophthalmol 2000; 238: 797-800.
    PubMedGoogle Scholar
  • 20 Schuster V, Mingers A-M, Seidenspinner S, Nüssgens Z, Pukrop T, Kreth HW. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood 1997; 90: 958-66.
    PubMedGoogle Scholar
  • 21 Schuster V, Seidenspinner S, Zeitler P, Escher C, Pleyer U, Bernauer W, Stiehm ER, Isenberg S, Seregard S, Olsson T, Mingers A-M, Schambeck C, Kreth HW. Compound-heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis. Blood 1999; 93: 3457-66.
    PubMedGoogle Scholar
  • 22 Scully C, Gokbuget AY, Allen C, Bagan JV, Efeoglu A, Erseven G, Flaitz C, Cintan S, Hodgson T, Porter SR, Speight P. Oral lesions indicative of plasminogen deficiency (hypoplasminogenemia). Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001; 91: 334-7.
    CrossrefPubMedGoogle Scholar
  • 23 Suh TT, Holmbäck K, Jensen NJ, Daugherty CC, Small K, Simon DI, Potter SS, Degen JL. Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 1995; 09: 2020-33.
    CrossrefPubMedGoogle Scholar
  • 24 Ploplis VA, Wilberding J, McLennan L, Liang Z, Cornelissen I, DeFord ME, Rosen ED, Castellino FJ. A total fibrinogen deficiency is compatible with the development of pulmonary fibrosis in mice. Am J Pathol 2000; 157: 703-8.
    CrossrefPubMedGoogle Scholar
  • 25 Bugge TH, Suh TT, Flick MJ, Daugherty CC, Romer J, Solberg H, Ellis V, Dano K, Degen JL. The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Biol Chem 1995; 270: 16886-94.
    CrossrefPubMedGoogle Scholar
  • 26 Dewerchin M, Van Nuffelen A, Wallays G, Bouché A, Moons L, Carmeliet P. Generation and characterization of urokinase receptor-deficient mice. J Clin Invest 1996; 97: 870-8.
    CrossrefPubMedGoogle Scholar
  • 27 Bugge TH, Flick MJ, Danton MJS, Daugherty CC, Romer J, Dano K, Carmeliet P, Collen D, Degen JL. Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Proc Natl Acad Sci USA 1996; 93: 5899-904.
    CrossrefPubMedGoogle Scholar
  • 28 Lijnen HR, Okada K, Matsuo O, Collen D, Dewerchin M. α2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding. Blood 1999; 93: 2274-81.
    CrossrefPubMedGoogle Scholar
  • 29 Dougherty KM, Pearson JM, Yang AY, Westrick RJ, Baker MS, Ginsburg D. The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival. Proc Natl Acad Sci USA 1999; 96: 686-91.
    CrossrefPubMedGoogle Scholar
  • 30 Lijnen HR, Carmeliet P, Bouche A, Moons L, Ploplis VA, Plow EF, Collen D. Restoration of thrombolytic potential in plasminogen-deficient mice by bolus administration of plasminogen. Blood 1996; 88: 870-6.
    PubMedGoogle Scholar
  • 31 Estreicher A, Mulhauser J, Carpentier JL, Orci L, Vassalli JD. The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol 1990; 111: 783-92.
    CrossrefPubMedGoogle Scholar
  • 32 Vassalli J-D, Dayer J-M, Wohlwend A, Belin D. Concomitant secretion of prourokinase and a plasminogen activator-specific inhibitor by cultured human monocytes-macrophages. J Exp Med 1984; 159: 1653-68.
    CrossrefPubMedGoogle Scholar
  • 33 Matsushima K, Taguchi M, Kovacs EJ, Young HA, Oppenheim JJ. Intracellular localization of human monocyte associated-interleukin (IL-1) activity and release of biologically active IL-1 from monocytes by trypsin and plasmin. J Immunol 1986; 136: 2883-91.
    PubMedGoogle Scholar
  • 34 Keski-Oja J, Lyons RM, Moses HL. Inactive secreted forms of transforming growth factor β: activation by proteolysis. J Cell Biochem 1987; 11A: 60.
    PubMedGoogle Scholar
  • 35 Ploplis VA, French EL, Carmeliet P, Collen D, Plow EF. Plasminogen deficiency differentially affects recruitment of inflammatory cell populations in mice. Blood 1998; 91: 2005-9.
    PubMedGoogle Scholar
  • 36 Lottenberg R, des Jardin LE, Wang H, Boyle MDP. Streptokinase-producing streptococci grown in human plasma acquire unregulated cellassociated plasmin activity. J Infect Dis 1992; 166: 436-40.
    CrossrefPubMedGoogle Scholar
  • 37 Sodeinde OA, Subrahmanyam YV, Stark K, Quan T, Bao Y, Goguen JD. A surface protease and the invasive character of plague. Science 1992; 258: 1004-7.
    CrossrefPubMedGoogle Scholar
  • 38 Gyetko MR, Chen GH, McDonald RA, Goodman R, Huffnagle GB, Wilkinson CC, Fuller JA, Toews GB. Urokinase is required for the pulmonary inflammatory response to Cryptococcus neoformans. A murine transgenic model. J Clin Invest 1996; 97: 1818-26.
    CrossrefPubMedGoogle Scholar
  • 39 Beck JM, Preston AM, Gyetko MR. Urokinase-type plasminogen activator in inflammatory cell recruitment and host defense against Pneumocystis carinii in mice. Infect Immun 1999; 67: 879-84.
    PubMedGoogle Scholar
  • 40 Gyetko MR, Libre EA, Fuller JA, Chen GH, Toews G. Urokinase is required for T lymphocyte proliferation and activation in vitro . J Lab Clin Med 1999; 133: 274-88.
    CrossrefPubMedGoogle Scholar
  • 41 Shapiro RL, Duquette JG, Nunes I, Roses DF, Harris MN, Wilson EL, Rifkin DB. Urokinase-type plasminogen activator-deficient mice are predisposed to staphylococcal botryomycosis, pleuritis, and effacement of lymphoid follicles. Am J Pathol 1997; 150: 359-69.
    PubMedGoogle Scholar
  • 42 Gyetko MR, Sud S, Kendall T, Fuller JA, Newstead MW, Standiford TJ. Urokinase receptor-deficient mice have impaired neutrophil recruitment in response to pulmonary Pseudomonas aeruginosa infection. J Immunol 2000; 165: 1513-9.
    CrossrefPubMedGoogle Scholar
  • 43 Gebbia JA, Monco JC, Degen JL, Bugge TH, Benach JL. The plasminogen activation system enhances brain and heart invasion in murine relapsing fever borreliosis. J Clin Invest 1999; 103: 81-7.
    CrossrefPubMedGoogle Scholar
  • 44 Roggwiller E, Fricaud A-C, Blisnick T, Braun-Breton B. Host urokinasetype plasminogen activator participates in the release of malaria merozoites from infected erythrocytes. Mol Biochem Parasitol 1997; 86: 49-59.
    CrossrefPubMedGoogle Scholar
  • 45 Rosenthal PJ, Semenov A, Ploplis VA, Plow EF. Plasminogen activators are not required in the erythrocytic life cycle of malaria parasites. Mol Biochem Parasitol 1998; 97: 253-7.
    CrossrefPubMedGoogle Scholar
  • 46 Piguet PF, Da Laperrousaz C, Vesin C, Tacchini-Cottier F, Senaldi G, Grau GE. Delayed mortality and attenuated thrombocytopenia associated with severe malaria in urokinase- and urokinase receptor-deficient mice. Infect Immuno 2000; 68: 3822-9.
    PubMedGoogle Scholar
  • 47 D’Costa SS, Boyle MD. Interaction of a group A streptococcus within human plasma results in assembly of a surface plasminogen activator that contributes to occupancy of surface plasmin binding structures. Microbial Pathogen 1998; 24: 341-9.
    CrossrefPubMedGoogle Scholar
  • 48 Li Z, Ploplis VA, French EL, Boyle MD. Interaction between group A streptococci and the plasmin(ogen) system promotes virulence in a mouse skin infection model. J Infect Dis 1999; 179: 907-14.
    CrossrefPubMedGoogle Scholar
  • 49 Wistedt AC, Kotarsky H, Marti D, Ringdahl U, Castellino FJ, Schaller J, Sjobring U. Kringle 2 mediates high affinity binding of plasminogen to an internal sequence in streptococcal surface protein PAM. J Biol Chem 1998; 273: 24420-4.
    CrossrefPubMedGoogle Scholar
  • 50 Ringdahl U, Svensson M, Wistedt AC, Renn T, Kellner R, Muller-Esterl W, Sjobring U. Molecular cooperation between protein PAM and streptokinase for plasmin acquisition by streptococcus pyogenes. J Biol Chem 1998; 273: 6424-30.
    CrossrefPubMedGoogle Scholar
  • 51 Goguen JD, Bugge T, Degen JL. Role of pleiotropic effects of plasminogen deficiency in infection experiments with plasminogen-deficient mice. Methods 2000; 21: 179-83.
    CrossrefPubMedGoogle Scholar
  • 52 Carmeliet P, Moons L, Ploplis V, Plow E, Collen D. Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J Clin Invest 1997; 99: 200-8.
    CrossrefPubMedGoogle Scholar
  • 53 Busuttil SJ, Drumm C, Ploplis VA, Plow EF. Endoluminal arterial injury in plasminogen deficient mice. J Surg Res 2000; 91: 159-64.
    CrossrefPubMedGoogle Scholar
  • 54 Carmeliet P, Moons L, Herbert JM, Crawley J, Lupu F, Lijnen R, Collen D. Urokinase but not tissue plasminogen activator mediates arterial neointima formation in mice. Circ Res 1997; 81: 829-39.
    CrossrefPubMedGoogle Scholar
  • 55 Carmeliet P, Moons L, Dewerchin M, Rosenberg S, Herbert JM, Lupu F, Collen D. Receptor-independent role of urokinase-type plasminogen activator in pericellular plasmin and matrix metalloproteinase proteolysis during vascular wound healing in mice. J Cell Biol 1998; 140: 233-45.
    CrossrefPubMedGoogle Scholar
  • 56 Lijnen HR, Van Hoef B, Dewerchin M, Collen D. Alpha(2)-antiplasmin gene deficiency in mice does not affect neointima formation after vascular injury. Arterioscler Thromb Vasc Biol 2000; 20: 1488-92.
    CrossrefPubMedGoogle Scholar
  • 57 Carmeliet P, Moons L, Lijnen R, Janssens S, Lupu F, Collen D, Gerard RD. Inhibiting role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice. Circ 1997; 96: 2772-4.
    PubMedGoogle Scholar
  • 58 Eitzman DT, Westrick RJ, Xu Z, Tyson J, Ginsburg D. Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Blood 2000; 96: 4212-5.
    PubMedGoogle Scholar
  • 59 Ploplis VA, Cornelissen I, Sandoval-Cooper MJ, Weeks L, Noria FA, Castellino FJ. Remodeling of the vessel wall after copper-induced injury is highly attenuated in mice with a total deficiency of plasminogen activator inhibitor-1. Am J Pathol 2001; 158: 107-17.
    CrossrefPubMedGoogle Scholar
  • 60 Moons L, Shi C, Ploplis V, Plow E, Haber E, Collen D. Reduced transplant arteriosclerosis in plasminogen-deficient mice. J Clin Invest 1998; 102: 1788-97.
    CrossrefPubMedGoogle Scholar
  • 61 Shi C, Patel A, Zhang D, Wang H, Carmeliet P, Reed GL, Lee M-E, Haber E, Sibinga NES. Plasminogen is not required for neointima formation in a mouse model of vein graft stenosis. Circ Res 1999; 84: 883-90.
    CrossrefPubMedGoogle Scholar
  • 62 Xiao Q, Danton MJS, Witte DP, Kowala MC, Valentine MT, Bugge TH, Degen JL. Plasminogen deficiency accelerates vessel wall disease in mice predisposed to atherosclerosis. Proc Natl Acad Sci USA 1997; 94: 10335-40.
    CrossrefPubMedGoogle Scholar
  • 63 Xiao Q, Danton MJ, Witte DP, Kowala MC, Valentine MT, Degen JL. Fibrinogen deficiency is compatible with the development of atherosclerosis in mice. J Clin Invest 1998; 101: 1184-94.
    CrossrefPubMedGoogle Scholar
  • 64 Lou XJ, Boonmark NW, Horrigan FT, Degen JL, Lawn RM. Fibrinogen deficiency reduces vascular accumulation of apolipoprotein(a) and development of atherosclerosis in apolipoprotein(a) transgenic mice. Proc Natl Acad Sci USA 1998; 95: 12591-5.
    CrossrefPubMedGoogle Scholar
  • 65 Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, Dano K. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med 1996; 02: 287-92.
    CrossrefPubMedGoogle Scholar
  • 66 Bugge TH, Flick MJ, Danton MJ, Daugherty CC, Romer J, Dano K, Carmeliet P, Collen D, Degen JL. Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Proc Natl Acad Sci USA 1996; 93: 5899-904.
    CrossrefPubMedGoogle Scholar
  • 67 Bugge TH, Kombrinck KW, Flick MJ, Daugherty CC, Danton MJ, Degen JL. Loss of fibrinogen rescues the pleiotropic effects of plasminogen deficiency. Cell 1996; 87: 709-19.
    CrossrefPubMedGoogle Scholar
  • 68 Drew AF, Schiman HL, Kombrinck KW, Bugge TH, Degen JL, Kaufman AH. Persistent corneal haze after excimer laser photokeratectomy in plasminogen-deficient mice. Invest Ophthalmol Vis Sci 2000; 41: 67-72.
    PubMedGoogle Scholar
  • 69 Kao WW, Kao CW, Kaufman AH, Kombrinck KW, Converse RL, Good WV, Bugge TH, Degen JL. Healing of corneal epithelial defects in plasminogenand fibrinogen-deficient mice. Invest Ophthalmol Vis Sci 1998; 39: 502-8.
    PubMedGoogle Scholar
  • 70 Bezerra JA, Bugge TH, Melin-Aldana H, Sabla G, Kombrinck KW, Witte DP, Degen JL. Plasminogen deficiency leads to impaired remodeling after toxic injury to the liver. Proc Natl Acad Sci USA 1999; 96: 15143-8.
    CrossrefPubMedGoogle Scholar
  • 71 Creemers E, Cleutjens J, Smits J, Heymans S, Moons L, Collen D, Daemen M, Carmeliet P. Disruption of plasminogen gene in mice abolishes wound healing after myocardial infarction. Am J Pathol 2000; 156: 1865-73.
    CrossrefPubMedGoogle Scholar
  • 72 Roselli HT, Su M, Washington K, Kerins DM, Vaughan DE, Russell WE. Liver regeneration is transiently impaired in urokinase-deficient mice. Am J Physiol 1998; 275: G1472-G1479.
    PubMedGoogle Scholar
  • 73 Sappino A, Madani R, Huarte J, Belin D, Kiss J, Wohlwend A, Vassali J-D. Extracellular proteolysis in the adult murine brain. J Clin Invest 1993; 92: 679-85.
    CrossrefPubMedGoogle Scholar
  • 74 Tsirka SE, Rogove AD, Bugge TH, Degen J, Strickland S. An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J Neurosci 1997; 17: 543-52.
    CrossrefPubMedGoogle Scholar
  • 75 Tsirka SE, Gualandris A, Amaral DG, Strickland S. Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 1995; 377: 340-4.
    CrossrefPubMedGoogle Scholar
  • 76 Tsirka SE, Bugge TH, Degen JL, Strickland S. Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin. Proc Natl Acad Sci USA 1997; 94: 9779-81.
    CrossrefPubMedGoogle Scholar
  • 77 Chen ZL, Strickland S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 1997; 26: 917-25.
    PubMedGoogle Scholar
  • 78 Akassoglou K, Kombrinck KW, Degen JL, Strickland S. Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury. J Cell Biol 2000; 149: 1157-66.
    CrossrefPubMedGoogle Scholar
  • 80 Yu W, Kim J, Ossowski L. reduction in surface urokinase receptor forces malignant cells into a protracted state of dormancy. J Cell Biol 1997; 137: 767-77.
    CrossrefPubMedGoogle Scholar
  • 81 Swiercz R, Wolfe JD, Zaher A, Jankun J. Expression of the plasminogen activation system in kidney cancer correlates with its aggressive phenotype. Clin Cancer Res 1998; 04: 869-77.
    PubMedGoogle Scholar
  • 82 Shapiro RL, Duquette JG, Roses DF, Nunes I, Harris MN, Kamino H, Wilson EL, Rifkin DB. Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and WT mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals. Cancer Res 1996; 56: 3597-604.
    PubMedGoogle Scholar
  • 83 Frandsen TL, Holst-Hansen C, Nielsen BS, Christensen IJ, Nyengaard JR, Carmeliet P, Brunner N. Direct evidence of the importance of stromal urokinase plasminogen activator (uPA) in the growth of an experimental human breast cancer using a combined uPA gene-disrupted and immunodeficient xenograft model. Cancer Res 2001; 61: 532-7.
    PubMedGoogle Scholar
  • 84 Gutierrez Ls, Schulman A, Brito-Robinson T, Noria F, Ploplis VA, Castellino FJ. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Cancer Res 2000; 60: 5839-47.
    PubMedGoogle Scholar
  • 85 Bajou K, Noel A, Gerard RD, Masson V, Brunner N, Holst-Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D, Foidart JM. Absence of host plasminogen activator inhibitor-1 prevents cancer invasion and vascularization. Nat Med 1998; 04: 923-8.
    CrossrefPubMedGoogle Scholar
  • 86 Bajou K, Masson V, Gerard RD, Schmitt PM, Albert V, Praus M, Lund LR, Frandsen TL, Brunner N, Dano K, Fusenig NE, Weidle U, Carmeliet P, Loskutoff D, Collen D, Carmeliet P, Foidart JM, Noel A. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J Cell Biol 2001; 152: 777-84.
    CrossrefPubMedGoogle Scholar
  • 87 Eitzman DT, Krauss JC, Shen T, Cui J, Ginsburg D. Lack of plasminogen activator inhibitor-1 effect in a transgenic mouse model of metastatic melanoma. Blood 1996; 87: 4718-22.
    PubMedGoogle Scholar
  • 88 Bugge TH, Kombrinck KW, Xiao Q, Holmbäck K, Daugherty CC, Witte DP, Degen JL. Growth and dissemination of Lewis Lung Carcinoma in plasminogen-deficient mice. Blood 1997; 90: 4522-31.
    PubMedGoogle Scholar
  • 89 Palumbo JS, Kombrinck KW, Drew AF, Grimes TS, Kiser JH, Degen JL, Bugge TH. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 2000; 96: 3302-9.
    PubMedGoogle Scholar
  • 90 Bugge TH, Lund LR, Kombrinck KW, Nielsen BS, Holmbäck K, Drew AF, Flick MJ, Witte MDP, Dano K, Degen JL. Reduced metastasis of polyoma virus middle T antigen-induced mammary cancer in plasminogen-deficient mice. Oncogene 1998; 16: 3097-104.
    CrossrefPubMedGoogle Scholar
  • 91 Kincaid-Smith P. Coagulation and renal disease. Kidney Int 1972; 02: 183-90.
    CrossrefPubMedGoogle Scholar
  • 92 Holdsworth SR, Thomson NM, Glasgow EF, Atkins RC. The effect of defibrination on macrophage participation in rabbit nephrotoxic nephritis: studies using glomerular culture and electron microscopy. Clin Exp Immunol 1979; 37: 38-43.
    PubMedGoogle Scholar
  • 93 Thomson NM, Moran J, Simpson IJ, Peters DK. Defibrination with ancrod in experimental immune complex nephritis. Clin Exp Immunol 1975; 20: 527-57.
    PubMedGoogle Scholar
  • 94 Naish P, Penn GB, Evans DJ, Peters DK. The effect of defibrination on nephrotoxic serum nephritis in rabbits. Clin Sci 1972; 42: 643-6.
    CrossrefPubMedGoogle Scholar
  • 95 Malliaros J, Holdsworth SR, Wojta J, Erlich J, Tipping PG. Glomerular fibrinolytic activity in antiGBM glomerulonephritis in rabbits. Kidney Int 1993; 44: 557-64.
    CrossrefPubMedGoogle Scholar
  • 96 Rondeau E, Mougenot B, Lacave R, Peraldi MN, Kruithof EKO, Sraer JD. Plasminogen activator inhibitor 1 in renal deposits of human nephropathies. Clin Nephrol 1990; 33: 55-60.
    PubMedGoogle Scholar
  • 97 Kitching R, Holdsworth SR, Ploplis VA, Plow EF, Collen D, Carmeliet P, Tipping PG. Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis. J Exp Med 1997; 185: 963-8.
    CrossrefPubMedGoogle Scholar
  • 98 Idell S, James KK, Gilles C, Fair DS, Thrall RS. Abnormalities of pathways of fibrin turnover in lung lavage of rats with oleic acid and bleomycin-induced lung injury support alveolar fibrin deposition. Am J Pathol 1989; 135: 387-99.
    PubMedGoogle Scholar
  • 99 Idell S, James KK, Levin EG, Schwartz BS, Manchanda N, Maunder RJ, Martin TR, McLarty J, Fair DS. Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest 1989; 84: 695-705.
    CrossrefPubMedGoogle Scholar
  • 100 Idell S, Peters J, James KK, Fair DS, Coalson JJ. Local abnormalities of coagulation and fibrinolytic pathways that promote alveolar fibrin deposition in the lungs of baboons with diffuse alveolar damage. J Clin Invest 1989; 84: 181-93.
    CrossrefPubMedGoogle Scholar
  • 101 Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D, Simon RH. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1. J Clin Invest 1996; 97: 232-7.
    CrossrefPubMedGoogle Scholar
  • 102 Hart DA, Whidden P, Green F, Henkin J, Woods DE. Partial reversal of established bleomycin-induced pulmonary fibrosis by rh-urokinase in a rat model. Clin Invest Med 1994; 17: 69-76.
    PubMedGoogle Scholar
  • 103 Sisson TH, Hattori N, Xu Y, Simon RH. Teratment of bleomycin-induced pulmonary fibrosis by transfer of urokinase-type plasminogen activator genes. Hum Gene Ther 1999; 10: 2315-23.
    CrossrefPubMedGoogle Scholar
  • 104 Swaisgood CM, French EL, Noga C, Simon RH, Ploplis VA. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system. Am J Pathol 2000; 157: 177-87.
    CrossrefPubMedGoogle Scholar
  • 105 Ploplis VA, Wilberding J, McLennan L, Liang Z, Cornelissen I, DeFord ME, Rosen ED, Castellino FJ. A total fibrinogen deficiency is compatible with the development of pulmonary fibrosis in mice. Am J Pathol 2000; 157: 703-8.
    CrossrefPubMedGoogle Scholar
  • 106 Hattori N, Degen JL, Sisson TH, Liu H, Moore BB, Pandrangi RG, Simon RH, Drew AF. Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice. J Clin Invest 2000; 106: 1341-50.
    CrossrefPubMedGoogle Scholar
  • 107 Firestein GS. Etiology and pathogenesis of rheumatoid arthritis. In: Textbook of Rheumatology. Kelley WN, Harris ED, Ruddy S, Sledge CB. eds. Philadelphia: W. B. Saunders; 1997: 851-97.
    Google Scholar
  • 108 Clemmensen I, Holund D, Andersen RB. Fibrin and fibronectin in rheumatoid synovial membrane and rheumatoid synovial fluid. Arthritis Rheum 1983; 26: 479-85.
    CrossrefPubMedGoogle Scholar
  • 109 Weinberg JB, Pippen AM, 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
  • 110 Salvi R, Péclat V, So A, Busso N. Enhanced expression of genes involved in coagulation and fibrinolysis in murine arthritis. Arthritis Res 2000; 02: 504-12.
    CrossrefPubMedGoogle Scholar
  • 111 Busso N, Péclat V, Van Ness K, Kolodziesczyk E, Degen J, Bugge T, So A. Exacerbation of antigen-induced arthritis in urokinase-deficient mice. J Clin Invest 1998; 102: 41-50.
    CrossrefPubMedGoogle Scholar