Structure and function of the plasminogen/plasmin system

Francis J. Castellino; Victoria A. Ploplis

doi:10.1160/TH04-12-0842

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 93(04): 647-654
DOI: 10.1160/TH04-12-0842

Theme Issue Article

Schattauer GmbH

Structure and function of the plasminogen/plasmin system

Francis J. Castellino

¹W. M. Keck Center for Transgene Research and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

,

Victoria A. Ploplis

¹W. M. Keck Center for Transgene Research and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

› Author Affiliations

Abstract

Summary

Activation of the fibrinolytic system is dependent on the conversion of the plasma zymogen, plasminogen (Pg), to the serine protease plasmin (Pm) by the physiological activators urokinase-type Pg activator (uPA) or tissue-type plasminogen activator (tPA). The primary in vivo function of Pm is to regulate vascular patency by degrading fibrin-containing thrombi. However, the identification of Pg/Pm receptors and the ability of Pm to degrade other matrix proteins have implicated Pm in other functions involving degradation of protein barriers, thereby mediating cell migration, an important event in a number of normal e.g., embryogenesis, wound healing, angiogenesis, and pathological, e.g., tumor growth and dissemination, processes. Prior to the development of Pg-deficient mice, much of the evidence for its role in other biological events was based on indirect studies. With the development and characterization of these mice, and ability to apply challenges utilizing a number of animal models that mimic the human condition, a clearer delineation of Pg/Pm function has evolved and has contributed to an understanding of mechanisms associated with a number of pathophysiological events.

Keywords

Plasminogen - fibrinolysis - kringle domains - gene targeting - cell invasion

Full Text

References

References
1 Forsgren M, Raden B, Israelsson M. et al. Molecular cloning and characterization of a full-length cDNA clone for human plasminogen. FEBS Lett 1987; 213: 254-60.
2 Bohmfalk JF, Fuller GM. Plasminogen is synthesized by primary cultures of rat hepatocytes. Science 1980; 209: 408-10.
3 Raum DD. et al. Synthesis of human plasminogen by the liver. Science 1980; 208: 1036-37.
4 Saito H, Hamilton SM, Tavill AS. et al. Production and release of plasminogen by isolated perfused rat liver. Proc Natl Acad Sci USA 1980; 77: 6837-40.
5 Zhang L, Seiffert D, Fowler BJ. et al. Plasminogen has a broad extrahepatic distributions. Thromb Haemost 2002; 87: 493-501.
6 Hayes ML, Castellino FJ. Carbohydrate of human plasminogen variants. I. Carbohydrate composition and glycopeptide isolation and characterization. J Biol Chem 1979; 254: 8768-71.
7 Hayes ML, Castellino FJ. Carbohydrate of human plasminogen variants. II. Structure of the asparaginelinked oligosaccharide unit. J Biol Chem 1979; 254: 8772-76.
8 Pirie-Shepherd SR, Stevens RD, Andon NL. et al. Evidence for a novel O-linked sialylated trisaccharide on Ser-248 of human plasminogen 2. J Biol Chem 1997; 272: 7408-11.
9 Hortin GL. Isolation of glycopeptides containing O-linked oligosaccharides by lectin affinity chromatography on jacalin-agarose. Anal Biochem 1990; 191: 262-67.
10 Wang H. et al. Serine-578 is a major phosphorylation locus in human plasma plasminogen. Biochemistry 1997; 36: 8100-06.
11 Sottrup-Jensen L. et al. The primary structure of human plasminogen: isolation of two lysine-binding fragments and one „mini“ plasminogen (MW, 38000) by elastase-catalyzed-specific limited proteolysis. Prog Chem Fibrinolysis Thrombolysis 1978; 3: 191-209.
12 Magnusson S, Petersen TE, Sottrup-Jensen L. et al. Complete primary structure of prothrombin: Isolation and reactivity of ten carboxylated glutamic residues and regulation of prothrombin activation by thrombin. in Proteases and Biological Control (Reich, E, Rifkin, DB, & Shaw, E, Eds). 1975. Cold Spring Harbor Laboratories; Cold Spring Harbor, NY: 123-49
13 McMullen BA, Fujikawa K. Amino acid sequence of the heavy chain of human a-factor XIIa (activated Hageman factor). J Biol Chem 1985; 260: 5328-41.
14 Pennica D, Holmes WE, Kohr WJ. et al. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 1983; 301: 214-21.
15 Steffens GJ, Gunzler WA, Otting F. et al. The complete amino acid sequence of low molecular mass urokinase from human urine. Hoppe-Seyler's Z Physiol Chem 1982; 363: 1043-58.
16 McLean JW, Tomlinson JE, Kuang W-j. et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 330: 132-37.
17 Suenson E, Thorsen S. Secondary-site binding of glu-plasmin, lys-plasmin and miniplasmin to fibrin. Biochem J 1981; 197: 619-28.
18 Berge A, Sjobring U. PAM, a novel plasminogenbinding protein from Streptococcus pyogenes. J Biol Chem 1993; 268: 25417-24.
19 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. Microb Pathog 1998; 24: 341-49.
20 Wistedt AC, Kotarsky H, Marti D. et al. Kringle 2 mediates high affinity binding of plasminogen to an internal sequence in streptococcal surface protein PAM. J Biol Chem 1998; 273: 24420-24.
21 Miles LA, Dahlberg CM, Plow EF. The cell binding domains of plasminogen and their function in plasma. J Biol Chem 1988; 263: 11928-34.
22 Urano T, Chibber BAK, Castellino FJ. The reciprocal effects of ε -aminohexanoic acid and chloride ion on the activation of human [Glu 1 ]plasminogen by human urokinase. Proc Natl Acad Sci USA 1987; 84: 4031-34.
23 Urano T, De Serrano VS, Chibber BAK. et al. The control of the urokinase-catalyzed activation of human glutamic acid 1-plasminogen by positive and negative effectors. J Biol Chem 1987; 262: 15959-64.
24 O'Reilly MS, Holmgren L, Shing Y. et al. Angiostatin: A novel angiogenesis inhibitor that mediates the supression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315-28.
25 Ji WR. et al. Selective inhibition by kringle 5 of human plasminogen on endothelial cell migration, an important process in angiogenesis. Biochem Biophys Res Comm 1998; 247: 414-19.
26 Ji WDR, Castellino FJ, Chang Y. et al. Characterization of kringle domains of angiostatin as antagonists of endothelial cell migration, an important process in angiogenesis. FASEB J 1998; 12: 1731-38.
27 Sehl LC, Castellino FJ. Thermodynamic properties of the binding of α -, ω -amino acids to the isolated kringle 4 region of human plasminogen as determined by high sensitivity titration calorimetry. J Biol Chem 1990; 265: 5482-86.
28 Menhart N. et al. Construction, expression and purification of recombinant kringle 1 of human plasminogen and analysis of its interaction with ω -amino acids. Biochemistry 1991; 30: 1948-57.
29 Menhart N. et al. Functional independence of the kringle 4 and kringle 5 regions of human plasminogen. Biochemistry 1993; 32: 8799-806.
30 Menhart N, Castellino FJ. The importance of the hydrophobic components of the binding energies in the interaction of ω -amino acid ligands with isolated kringle polypeptide domains of human plasminogen. Int J Pept Protein Res 1995; 46: 464-70.
31 Marti DN, Schaller J, Llinas M. Solution structure and dynamics of the plasminogen kringle 2-AMCHA complex: 3(1)-helix in homologous domains. Biochemistry 1999; 38: 15741-55.
32 Chang Y, Mochalkin I, McCance SG. et al. Structure and ligand binding determinants of the recombinant kringle 5 domain of human plasminogen. Biochemistry 1998; 37: 3258-71.
33 Violand BN, Castellino FJ. Mechanism of urokinase- catalyzed activation of human plasminogen. J Biol Chem 1976; 251: 3906-12.
34 Weisel JW. et al. Interactions of plasminogen with polymerizing fibrin and its derivatives, monitored with a photoaffinity cross-linker and electron microscopy. J Mol Biol 1994; 235: 1117-35.
35 Ponting CP, Holland SK, Cederholm-Williams SA. et al. The compact domain conformation of human glu-plasminogen in solution. Biochim Biophys Acta 1992; 1159: 155-61.
36 Mangel WF, Lin B, Ramakrishnan V. Characterization of an extremely large, ligand-induced conformational change in plasminogen. Science 1990; 248: 69-73.
37 Ramakrishnan V, Patthy L, Mangel WF. Conformation of Lys-plasminogen and the kringle 1–3 fragment of plasminogen analyzed by small-angle neutron scattering. Biochemistry 1991; 30: 3963-69.
38 Violand BN, Sodetz JM, Castellino FJ. The effect of epsilon aminocaproic acid on the gross conformation of plasminogen and plasmin. Arch Biochem Biophys 1975; 170: 300-05.
39 Misselwitz R, Welfle K, Welfle H. Conformations and stabilities of human glu(1)- and lys(78)-plasminogen and of the fragments mini- and microplasminogen, analysed by circular dichroism and differential scanning calorimetry. Int J Biol Macromol 1994; 16: 187-94.
40 Murray JC. et al. Linkage disequilibrium of plasminogen polymorphisms and assignment of the gene to human chromosome 6q26–6q27. Am J Hum Genet 1987; 40: 338-50.
41 Petersen TE. et al. Characterization of the gene for human plasminogen, a key proenzyme in the fibrinolytic system. J Biol Chem 1990; 265: 6104-11.
42 Meroni G, Buraggi G, Mantovani R. et al. Motifs resembling hepatocyte nuclear factor 1 and activator protein 3 mediate the tissue specificity of the human plasminogen gene. Eur J Biochem 1996; 236: 373-82.
43 Kida M, Wakabayashi S, Ichinose A. Characterization of the 5'-flanking regions of plasminogen-related genes A and B. FEBS Lett 1997; 404: 95-99.
44 Jenkins GR, Seiffert D, Parmer RJ. et al. Regulation of plasminogen gene expression by interleukin-6. Blood 1997; 89: 2394-403.
45 Ploplis VA. et al. Plasminogen deficiency differentially affects recruitment of inflammatory cell populations in mice. Blood 1998; 91: 2005-9.
46 Romer J, Bugge TH, Pyke C. et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nature Med 1996; 2: 287-92.
47 Lund LR. et al. Lactational competence and involution of the mouse mammary gland require plasminogen. Development 2000; 127: 4481-92.
48 Creemers E. et al. Disruption of the plasminogen gene in mice abolishes wound healing after myocardial infarction. Am J Pathol 2000; 156: 1865-73.
49 Ranson M. et al. Increased plasminogen binding is associated with metastatic breast cancer cells: differential expression of plasminogen binding proteins. Br J Cancer 1998; 77: 1586-97.
50 Jiang Q. et al. The local chromaffin cell plasminogen/ plasmin system and the regulation of catecholamine secretion. Ann NY Acad Sci 2002; 971: 445-9.
51 Weide I. et al. Plasmin is a specific stimulus of the 5-lipoxygenase pathway of human peripheral monocytes. Thromb Haemost 1996; 76: 561-68.
52 Syrovets T. et al. Plasmin is a potent and specific chemoattractant for human peripheral monocytes acting via a cyclic guanosine monophosphate-dependent pathway. Blood 1997; 89: 4574-83.
53 Syrovets T. et al. Plasmin-induced expression of cytokines and tissue factor in human monocytes involves AP-1 and IKKbeta-mediated NF-kappaB activation. Blood 2001; 97: 3941-50.
54 Majumdar M, Tarui T, Shi B. et al. Plasmin-induced migration requires signaling through proteaseactivated receptor 1 and integrin alpha(9)beta(1). J Biol Chem 2004; 279: 37528-34.
55 Hajjar KA, Harpel PC, Jaffe EA. et al. Binding of plasminogen to cultured human endothelial cells. J Biol Chem 1986; 261: 11656-62.
56 Plow EF, Freany F, Plescia J. et al. The plasminogen system and cell surfaces: Evidence for plasminogen and urokinase receptors on the same cell type. J Cell Biol 1986; 103: 2411-30.
57 Miles LA, Plow EF. Receptor mediated binding of the fibrinolytic components, plasminogen and urokinase to peripheral blood cells. Thromb Haemost 1987; 58: 936-42.
58 Gonzalez-Gronow M, Gawdi G, Pizzo SV. Characterization of the plasminogen receptors of normal and rheumatoid-arthritis human synovial fibroblasts. J Biol Chem 1994; 269: 4360-66.
59 Hembrough TA, Vasudevan J, Allietta MM. et al. A cytokeratin 8-like protein with plasminogen-binding activity is present on the external surfaces of hepatocytes, HepG2 cells and breast carcinoma cell lines. J Cell Sci 1995; 108: 1071-82.
60 O'Mullane MJ, Baker MS. Loss of cell viability dramatically elevates cell surface plasminogen binding and activation. Exp Cell Res 1998; 242: 153-64.
61 O'Mullane MJ, Baker MS. Elevated plasminogen receptor expression occurs as a degradative phase event in cellular apoptosis. Immunol Cell Biol 1999; 77: 249-55.
62 Green H. Terminal differentiation of cultured human epidermal cells. Cell 1977; 11: 405-16.
63 Burgos H, Hsi BL, Yeh CJ. et al. Plasminogen binding by human amniochorion. A possible factor in premature rupture of membranes. Am J Obstet Gynecol 1982; 143: 958-63.
64 Plow EF, Miles LA. Plasminogen receptors in the mediation of pericellular proteolysis. Cell Differ Dev 1990; 32: 293-98.
65 Collen D, Verstraete M. Molecular biology of human plasminogen. II Metabolism in physiological and some pathophysiological conditions in man. Thromb Diath Haemorrh 1975; 34: 403-18.
66 Adelman B, Rizk A, Hanners E. Plasminogen interactions with platelets in plasma. Blood 1988; 72: 1530-35.
67 Miles LA, Dahlberg CM, Plescia J. et al. Role of cell-surface lysines in plasminogen binding to cells: Identification of α -enolase as a candidate plasminogen receptor. Biochemistry 1991; 30: 1682-91.
68 Redlitz A, Tan AK, Eaton DL. et al. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest 1995; 96: 2534-38.
69 Nakajima K. et al. Plasminogen binds specifically to alpha-enolase on rat neuronal plasma membrane. J Neurochem 1994; 63: 2048-57.
70 Hajjar KA, Jacovina AT, Chacko J. An endothelial cell receptor for plasminogen tissue plasminogen activator. Identity with annexin II.. J Biol Chem 1994; 269: 21191-97
71 Pluskota E. et al. Integrin α M β 2 orchestrates and accelerates plasminogen activation and fibrinolysis by neutrophils. J Biol Chem 2004; 279: 18063-72.
72 Dudani AK, Ganz PR. Endothelial cell surface actin serves as a binding site for plasminogen, tissue plasminogen activator and lipoprotein(a). Br J Haematol 1996; 95: 168-78.
73 Fan ZQ. et al. Tissue factor regulates plasminogen binding and activation. Blood 1998; 91: 1987-98.
74 Lishko VK, Novokhatny VV, Yakubenko VP. et al. Characterization of plasminogen as an adhesive ligand for integrins α M β 2 (Mac-1) and alpha5beta1 (VLA-5). Blood 2004; 104: 719-26.
75 Miles LA, Plow EF. Binding and activation of plasminogen on the platelet surface. J Biol Chem 1985; 260: 4303-11.
76 Duval-Jobe C, Parmely MJ. Regulation plasminogen activation by human U937 promonocytic cells. J Biol Chem 1994; 269: 21353-57.
77 Felez J, Miles LA, Fabregas P. et al. Characterization of cellular binding sites and interactive regions within reactants required for enhancement of plasminogen activation by tPA on the surface of leukocytic cells. Thromb Haemost 1996; 76: 577-84.
78 Sinniger V. et al. Regulation of tissue plasminogen activator activity by cells. Domains responsible for binding and mechanism of stimulation. J Biol Chem 1999; 274: 12414-22.
79 Ellis V. Cellular receptors for plasminogen activators. Recent advances. Trends Cardiovasc Med 1997; 7: 227-34.
80 Menhart N, Hoover GJ, McCance SG. et al. Roles of individual kringle domains in the functioning of positive and negative effectors of human plasminogen activation. Biochemistry 1995; 34: 1482-88.
81 Miles LA, Plow EF. Plasminogen receptors: ubiquitous sites for cellular regulation of fibrinolysis. Fibrinolysis 1988; 2: 61-71.
82 Zhang L. et al. Endogenous plasmin converts Gluplasminogen to Lys-plasmino-gen on the cell surface. J Thromb Haemost 2003; 1: 1264-70.
83 Aoki N. et al. Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis. J Clin Invest 1978; 61: 1186-95.
84 Miyata T, Iwanaga S, Sakata Y. et al. Plasminogen Tochigi: Inactive plasmin resulting from replacement of alanine-600 by threonine at the active site. Proc Natl Acad Sci USA 1982; 79: 6132-36.
85 Ichinose A, Espling ES, Takamatsu J. et al. Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis. Proc Natl Acad Sci USA 1991; 88: 115-19.
86 Mingers AM, Philapitsch A, Zeitler P. et al. Human homozygous type I plasminogen deficiency and ligneous conjunctivitis. APMIS 1999; 107: 62-72.
87 Kraft J. et al. Ligneous conjunctivitis in a girl with severe type I plasminogen deficiency. Graefes Arch Clin Exp Ophthalmol 2000; 238: 797-800.
88 Schuster V. et al. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood 1997; 90: 958-66.
89 Schuster V. et al. Prenatal diagnosis in a family with severe type I plasminogen deficiency, ligneous conjunctivitis and congenital hydrocephalus. Prenatal Diag 1999; 19: 483-87.
90 Ploplis VA. et al. Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 1995; 92: 2585-93.
91 Bugge TH. et al. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Gene Develop 1995; 9: 794-807.
92 Lijnen HR. et al. Restoration of thrombolytic potential in plasminogen-deficient mice by bolus administration of plasminogen. Blood 1996; 88: 870-76.
93 Zeng B. et al. Influence of plasminogen deficiency on the contribution of polymorphonuclear leucocytes to fibrin/ogenolysis: studies in plasminogen knock-out mice. Thromb Haemost 2002; 88: 805-10.
94 Carmeliet P. et al. Urokinase but not tissue plasminogen activator mediates arterial neointima formation in mice. Circ Res 1997; 81: 829-39.
95 Lijnen HR, VanHoef B, Dewerchin M. et al. alpha(2)-antiplasmin gene deficiency in mice does not affect neointima formation after vascular injury. Arterioscler Thromb Vasc Biol 2000; 20: 1488-92.
96 Ploplis VA. et al. 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.
97 Carmeliet P, Moons L, Ploplis V. et al. Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J Clin Invest 1997; 99: 200-8.
98 Busuttil SJ, Drumm C, Ploplis VA. et al. Endoluminal arterial injury in plasminogen-deficient mice. J Surg Res 2000; 91: 159-64.
99 Moons L, Shi C, Ploplis V. et al. Reduced transplant arteriosclerosis in plasminogen-deficient mice. J Clin Invest 1998; 102: 1788-97.
100 Shi C, Patel A, Zhang D. et al. Plasminogen is not required for neointima formation in a mouse model of vein graft stenosis. Circ Res 1999; 84: 883-90.
101 Xiao Q, Danton MJ, Witte DP. et al. Plasminogen deficiency accelerates vessel wall disease in mice predisposed to atherosclerosis. Proc Natl Acad Sci USA 1997; 94: 10335-40.
102 Matsushima K, Taguchi M, Kovacs EJ. et al. Intracellular localization of human monocyte associated interleukin 1 (IL 1) activity and release of biologically active IL 1 from monocytes by trypsin and plasmin. J Immunol 1986; 136: 2883-91.
103 Lyons RM, Keski-Oja J, Moses HL. Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J Cell Biol 1988; 106: 1659-65.
104 Busuttil SJ, Ploplis VA, Castellino FJ. et al. A central role for plasminogen in the inflammatory response to biomaterials. J Thromb Haemost 2004; 2: 1798-805.
105 Goguen JD, Bugge T, Degen JL. Role of the pleiotropic effects of plasminogen deficiency in infection experiments with plasminogen-deficient mice. Methods 2000; 21: 179-83.
106 Gebbia JA, Monco JCG, Degen JL. et al. The plasminogen activation system enhances brain and heart invasion in murine relapsing fever borreliosis. J Clin Invest 1999; 103: 81-7.
107 Nordstrand A. et al. Delayed invasion of the kidney and brain by Borellia crocidurae in plasminogendeficient mice. Infect Immunol 2001; 69: 5832-9.
108 Rosenthal PJ. et al. Plasminogen activators are not required in the erythrocytic life cycle of malaria parasites. Mol Biochem Parasitol 1998; 97: 253-7.
109 Roggwiller E, Fricaud AC, Blisnick T. et al. Host urokinase-type plasminogen activator participates in the release of malaria merozoites from infected erythrocytes. Mol Biochem Parasitol 1997; 86: 49-59.
110 Li ZQ, Ploplis VA, French EL. et al. 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.
111 Sun H. et al. Plasminogen is a critical host pathogenicity factor for Group A streptococcal infection. Science 2004; 305: 1283-6.
112 Sato J. et al. The fibrinolytic system in dissemination and matrix protein deposition during a mycobacterium infection. Am J Pathol 2003; 163: 517-31.
113 Kincaid-Smith P, Hobbs JB. Glomerulonephritis: a classification based on morphology with comments on the significance of vessel lesions. Med J Aust 1972; 2: 1397-403.
114 Rondeau E, Mougenot B, Lacave R. et al. Plasminogen activator inhibitor 1 in renal fibrin deposits of human nephropathies. Clin Nephrol 1990; 33: 55-60.
115 Malliaros J, Holdsworth SR, Wojta J. et al. Glomerular fibrinolytic activity in anti-GBM glomerulonephritis in rabbits. Kidney Int 1993; 44: 557-64.
116 Lee HS, Park SY, Moon KC. et al. mRNA expression of urokinase and plasminogen activator inhibitor- 1 in human crescentic glomerulonephritis. Histopathology 2001; 39: 203-9.
117 Kitching AR. et al. Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis. J Exp Med 1997; 185: 963-8.
118 Clemmensen I. et al. Fibrin and fibronectin in rheumatoid synovial membrane and rheumatoid synovial fluid. Arthritis Rheum 1983; 26: 479-85.
119 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.
120 Busso N, Peclat V, VanNess K. et al. Exacerbation of antigen-induced arthritis in urokinase-deficient mice. J Clin Invest 1998; 102: 41-50.
121 Idell S. et al. 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.
122 Idell S. et al. 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.
123 Idell S. et al. 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.
124 Eitzman DT. et al. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 1996; 97: 232-7.
125 Hart DA, Woods DE. Human urokinase, a serine proteinase, potentiates the in-vitro growth of micro-organisms which commonly infect burn patients. J Med Microbiol 1994; 41: 264-71.
126 Sisson TH, Hattori N, Xu Y. et al. Treatment of bleomycin-induced pulmonary fibrosis by transfer of urokinase-type plasminogen activator genes. Hum Gene Ther 1999; 10: 2315-23.
127 Swaisgood CM, French EL, Noga C. et al. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system. Am J Pathol 2000; 157: 177-87.
128 Ploplis VA. et al. A total fibrinogen deficiency is compatible with the development of pulmonary fibrosis in mice. Am J Pathol 2000; 157: 703-8.
129 Lund LR, Romer J, Bugge TH. et al. Functional overlap between two classes of matrix-degrading proteases in wound healing. EMBO J 1999; 18: 4645-56.
130 Bugge TH, Kombrinck KW, Flick MJ. et al. Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 1996; 87: 709-19.
131 Kao WWY. et al. Healing of corneal epithelial defects in plasminogen- and fibrinogen-deficient mice. Invest Ophthalmol Vis Sci 1998; 39: 502-8.
132 Drew AF, Schiman HL, Kombrinck KW. et al. Persistent corneal haze after excimer laser photokeratectomy in plasminogen-deficient mice. Invest Ophthalmol Vis Sci 2000; 41: 67-72.
133 Bezerra JA. et al. Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver. Proc Natl Acad Sci USA 1999; 96: 15143-8.
134 Salles FJ, Strickland S. Localization and regulation of the tissue plasminogen activator-plasmin system in the hippocampus. J Neurosci 2002; 22: 2125-34.
135 Tsirka SE. Clinical implications of the involvement of tPA in neuronal cell death. J Molecular Med 1997; 75: 341-7.
136 Tsirka SE. et al. Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin. Proc Natl Acad Sci USA 1997; 94: 9779-81.
137 Chen ZL, Strickland S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 1997; 91: 917-27.
138 Akassoglou K. et al. Tissue plasminogen activator- mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury. J Cell Biol 2000; 149: 1157-66.
139 Hoover-Plow J. et al. Selective behaviors altered in plasminogen-deficient mice are reconstituted with intracerebroventricular injection of plasminogen. Brain Res 2001; 898: 256-64.
140 Birnbaum SG, Davis M. Modulation of the acoustic startle reflex by infusion of corticotropin-releasing hormone into the nucleus reticularis pontis caudalis. Brain Res 1998; 782: 318-23.
141 Koob GF. Corticotropin-releasing factor, norepinephrine, and stress. Biol Psychiatry 1999; 46: 1167-80.
142 Wang N, Zhang L, Miles L. et al. Plasminogen regulates pro-opiomelanocortin processing. J Thromb Haemost 2004; 2: 785-96.
143 Ledesma MD. et al. Brain plasmin enhances APP α -cleavage and A β degradation and is reduced in Alzheimer's disease brains. EMBO Rep 2000; 1: 530-5.
144 Tucker HM. et al. Plasmin deficiency does not alter endogenous murine amyloid beta levels in mice. Neurosci Lett 2004; 368: 285-9.
145 Swiercz R, Wolfe JD, Zaher A. et al. Expression of the plasminogen activation system in kidney cancer correlates with its aggressive phenotype. Clin Cancer Res 1998; 4: 869-77.
146 Bugge TH, Kombrinck KW, Xiao Q. et al. Growth and dissemination of Lewis lung carcinoma in plasminogen- deficient mice. Blood 1997; 90: 4522-31.
147 Bugge TH, Lund LR, Kombrinck KK. et al. Reduced metastasis of Polyoma virus middle T antigeninduced mammary cancer in plasminogen-deficient mice. Oncogene 1998; 16: 3097-104.
148 Curino A. et al. Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages. Oncogene 2002; 21: 8830-42.
149 Oh CW, Hoover-Plow J, Plow EF. The role of plasminogen in angiogenesis in vivo. J Thromb Haemost 2003; 1: 1683-7.