Current view on alveolar coagulation and fibrinolysis in acute inflammatory and chronic interstitial lung diseases

Summary

Acute inflammatory and chronic interstitial lung diseases are characterized by excessive and persistent fibrin deposition in the lung.Intraalveolar fibrin accumulation,observed under these conditions, arises from a leakage of plasma proteins (including fibrinogen) into the alveolar space in combination with a disbalance of alveolar haemostasis. Tissue factor in association with factor VIIa and inhibition of urokinase by plasminogen activator inhibitor-1 are major factors that are responsible for the procoagulant and antifibrinolytic state. In addition, in acute respiratory distress syndrome (ARDS) patients, factor VII-activating protease and extracellular RNA, which may be released into the extracellular milieu from damaged cells during lung injury, may contribute to fibrin formation as well. Fibrin itself can increase vascular permeability, influence the expression of inflammatory mediators and alter the migration and proliferation of various cell types. Additionally, fibrin may inactivate pulmonary surfactant and provide a matrix on which fibroblasts can migrate and produce collagen.Furthermore,cellular activities of haemostatic proteases may also contribute to proinflammatory and fibrotic processes in the lung.The application of coagulation inhibitors, like tissue factor pathway inhibitor, active site-inactivated factor VIIa, activated protein C, antithrombin, heparin or hirudin turned out to be beneficial in experimental models of acute and chronic lung injury. However, the ability of anticoagulant and profibrinolytic agents to improve clinical outcome remains to be elucidated. In the current article, the role of the alveolar coagulation and fibrinolysis systems in acute inflammatory and chronic interstitial lung diseases is discussed with regard to pathomechanisms and modalities of intervention.

Keywords

Coagulation factors - coagulation inhibitors - fibrinogen / fibrin - haemostasis - lung

• References

• 1 Idell S, James KK, Levin EG. et al. Local abnormalities of coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest 1989; 84: 695-705.
• 2 Bertozzi P, Astedt B, Zenzius L. et al. Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med 1990; 322: 890-897.
• 3 Bernard GR, Artigas A, Brigham KL. et al. The American–European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149: 818-824.
• 4 Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342: 1334-1349.
• 5 Guenther A, Mosavi P, Ruppert C. et al. Enhanced tissue factor pathway activity and fibrin turnover in the alveolar compartment of patients with interstitial lung disease. Thromb Haemost 2000; 83: 853-860.
• 6 Hasday JD, Bachwich PR, Lynch III JP. et al. Procoagulant and plasminogen activator activities of bronchoalveolar fluid in patients with pulmonary sarcoidosis. Exp Lung Res 1988; 14: 261-278.
• 7 Nakstadt B, Lyberg T, Skjonsberg OH. et al. Local activation of the coagulation and fibrinolysis systems in lung disease. Thromb Res 1990; 57: 827-838.
• 8 Kotani I, Sato A, Hayakawa H. et al. Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosis. Thromb Res 1995; 77: 493-504.
• 9 Fujii M, Hayakawa H, Urano T. et al. Relevance of tissue factor and tissue factor pathway inhibitor for hypercoagulable state in the lungs of patients with idiopathic pulmonary fibrosis. Thromb Res 2000; 99: 111-117.
• 10 Imokawa S, Sato A, Hayakawa H. et al. Tissue factor expression and fibrin deposition in the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis. Am J Respir Crit Care Med 1997; 156: 631-636.
• 11 American Thoracic Society. Idiopathic pulmonary fibrosis: Diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161: 646-664.
• 12 Panos RJ, Mortenson RL, Niccoli SA. et al. Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment. Am J Med 1990; 88: 396-404.
• 13 Latsi PI, Du Bois RM, Nicholson AG. et al. Fibrotic idiopathic interstitial pneumonia. The prognostic value of longitudinal functional trends. Am J Respir Crit Care Med 2003; 168: 531-537.
• 14 Pardo A, Selman M. Idiopathic pulmonary fibrosis: new insights in its pathogenesis. Int. J. Biochem Cell Biol 2002; 34: 1534-1538.
• 15 Selman M, King TE, Pardo A. et al. Idiopathic pulmonary fibrosis: Prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134: 136-151.
• 16 Selman M, Pardo A, Barrera L. et al. Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med 2006; 173: 188-198.
• 17 Idell S, James KK, Gillies C. 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: 387-399.
• 18 Olman MA, Mackman N, Gladson CL. et al. Changes in procoagulant and fibrinolytic gene expression during bleomycin-induced lung injury in the mouse. J Clin Invest 1995; 96: 1621-1630.
• 19 De Waard V, Hansen HR, Spronk HHM. et al. Differential expression of tissue factor mRNA and protein expression in murine sepsis. The role of the granulocyte revisited. Thromb Haemost 2006; 95: 348-353.
• 20 Grainger DJ, Wakefield L, Bethell HW. et al. Release and activation of platelet latent TGF-beta in bloodclots during dissolution with plasmin. Nat Med 1995; 1: 932-937.
• 21 Seeger W, Elssner A, Guenther A. et al. Lung surfactant phospholipids associate with polymerizing fibrin – loss of surfactant activity. Am J Respir Cell Mol Biol 1993; 9: 213-220.
• 22 Burkhardt A. Alveolitis and collapse in the pathogenesis of pulmonary fibrosis. Am Rev Respir Dis 1989; 140: 513-524.
• 23 Leavell KJ, Peterson MW, Gross TJ. et al. The role of fibrin degradation products in neutrophil recruitment to the lung. Am J Respir Cell Mol Biol 1996; 14: 53-60.
• 24 Dang CV, Bell WR, Kaiser D. et al. Disorganisation of cultured vascular endothelial cell monolayers by fibrinogen fragment D. Science 1985; 227: 1487-1490.
• 25 Ciano PS, Colvin RB, Dvorak AM. et al. Macrophage migration in fibrin gel matrix. Lab Invest 1986; 54: 62-70.
• 26 Netzel-Arnett S, Mitola DJ, Yamada SS. et al. Collagen dissolution by keratinocytes requires cell surface plasminogen activation and matrix metalloproteinase activity. J Biol Chem 2002; 277: 45154-45161.
• 27 Legrand C, Polette M, Tournier JM. et al. uPA/plasmin system-mediated MMP-9 activation is implicated in bronchial epithelial cell migration. Exp Cell Res 2001; 264: 326-336.
• 28 Okumura Y, Sato H, Seiki M. et al. Proteolytic activation of the precursor of membrane type 1 matrix metalloproteinase by human plasmin. A possible cell surface activator. FEBS Lett 1997; 402: 181-184.
• 29 Yee JA, Yan L, Dominguez JC. et al. Plasminogendependent activation of latent transforming growth factor beta (TGF beta) by growing cultures of osteoblastlike cells. J Cell Physiol 1993; 157: 528-534.
• 30 Maquerlot F, Galiacy S, Malo M. et al. Dual role for plasminogen activator inhibitor type 1 as soluble and as matricellular regulator of epithelial alveolar cell wound healing. Am J Pathol 2006; 169: 1624-1632.
• 31 Chambers RC, Dabbagh K, McAnulty RJ. et al. Thrombin stimulates fibroblasts procollagen production via proteolytic activation of protease-activated receptor- 1. Biochem J 1998; 333: 121-127.
• 32 Blanc-Brude OP, Archer F, Leoni P. et al. Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signalling via PAR1 activation. Exp Cell Res 2005; 304: 16-27.
• 33 Bogatkevich GS, Tourkina E, Silver RM. et al. Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway. J Biol Chem 2001; 276: 45184-45192.
• 34 Chambers R, Leoni P, Blanc-Brude O. et al. Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1. J Biol Chem 2000; 275: 35584-35591.
• 35 Ludwicka-Bradley A, Tourkina E, Suzuki S. et al. Thrombin upregulates interleukin-8 in lung fibroblasts via cleavage of proteolytically activated receptor-I and protein kinase C-gamma activation. Am J Respir Cell Mol Biol 2000; 22: 235-243.
• 36 Shimizu T, Nishihira J, Watanabe H. et al. Macrophage migration inhibitory factor is induced by thrombin and factor Xa in endothelial cells. J Biol Chem 2004; 279: 13729-13737.
• 37 Monroe DM, Key NS. The tissue factor-factor VIIa complex: procoagulant activity, regulation, and multitasking. J Thromb Haemost 2007; 5: 1097-1105.
• 38 Howell DC, Johns RH, Lasky JA. et al. Absence of Proteinase-Activated Receptor-1 signalling affords protection from bleomycin-induced lung inflammation and fibrosis. Am J Pathol 2005; 166: 1353-1365.
• 39 Hattori N, Degen JL, Sisson TH. et al. Bleomycininduced pulmonary fibrosis in fibrinogen-null mice. J Clin Invest 2000; 106: 1341-1350.
• 40 Rao LV, Rapaport SI. Activation of factor VII bound to tissue factor: a key early step in the tissue factor pathway of blood coagulation. Proc Natl Acad Sci USA 1988; 85: 6687-6691.
• 41 Osnes LT, Westvik AB, Joø GB. et al. Inhibition of IL-1 induced tissue factor (TF) synthesis and procoagulant activity (PCA) in purified human monocytes by IL-4, IL-10 and IL-13. Cytokine 1996; 8: 822-827.
• 42 Samad F, Pandey M, Loskutoff DJ. Tissue factor gene expression in the adipose tissues of obese mice. Proc Natl Acad Sci USA 1998; 95: 7591-7596.
• 43 Wygrecka M, Markart P, Ruppert C. et al. Compartment- and cell-specific expression of coagulation and fibrinolysis factors in the murine lung undergoing inhalational versus intravenous endotoxin application. Thromb Haemost 2004; 92: 529-540.
• 44 Wygrecka M, Markart P, Ruppert C. et al. Cellular origin of pro-coagulant and (anti)-fibrinolytic factors in bleomycin-injured lungs. Eur Respir J 2007; 29: 1105-1114.
• 45 Gando S, Kameue T, Matsuda N. et al. Imbalance between the levels of tissue factor and tissue factor pathway inhibitor in ARDS patients. Thromb Res 2003; 109: 119-124.
• 46 Wygrecka M, Markart P, Fink L. et al. Raised protein levels and altered cellular expression of factor VII Activating Protease (FSAP) in the lungs of patients with acute respiratory distress syndrome (ARDS). Thorax 2007; 62: 880-888.
• 47 Choi-Miura NH, Tobe T, Sumiya J. et al. Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine-protease domain, similar to hepatocyte growth factor. J Biochem 1996; 119: 1157-1165.
• 48 Römisch J, , Feussner A, Vermöhlen S. et al. A protease isolated from human plasma activating factor VII independent of tissue factor. Blood Coagul Fibrinolysis 1999; 10: 471-479.
• 49 Kannemeier C, Feussner A, Stöhr HA. et al. FVIIand single-chain plasminogen activator activating protease (FSAP): activation and autoactivation of the proenzyme. Eur J Biochem 2001; 268: 3789-3796.
• 50 Etscheid M, Hunfeld A, König H. et al. Activation of proPHBSP, the zymogen of a plasma hyaluronan binding serine protease, by an intermolecular autocatalytic mechanism. Biol Chem 2000; 381: 1223-1231.
• 51 Choi-Miura NH, Takahashi K, Yoda M. et al. Proteolytic activation and inactivation of the serine protease activity of plasma hyaluronan binding protein. Biol Pharm Bull 2001; 24: 448-452.
• 52 Nakazawa F, Kannemeier C, Shibamiya A. et al. Extracellular RNA is a natural cofactor for the (auto-)activation of factor VII-activating protease (FSAP). Biochem J 2005; 385: 831-838.
• 53 Römisch J, Vermöhlen S, Feussner A. et al. The FVII activating protease cleaves single-chain plasminogen activators. Haemostasis 1999; 29: 292-299.
• 54 Kannemeier C, Al-Fakhri N, Preissner KT. et al. Factor VII-activating protease (FSAP) inhibits growth factor-mediated cell proliferation and migration of vascular smooth muscle cells. FASEB J 2004; 18: 728-730.
• 55 Etscheid M, Beer N, Kress JA. et al. Inhibition of bFGF/EGF-dependent endothelial cell proliferation by the hyaluronan-binding protease from human plasma. Eur J Cell Biol 2004; 82: 597-604.
• 56 Wygrecka M, Morty RE, Markart P. et al. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of factor VII-activating protease in patients with acute respiratory distress syndrome. J Biol Chem 2007; 282: 21671-21682.
• 57 Kannemeier C, Shibamiya A, Nakazawa F. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 2007; 104: 6388-6393.
• 58 Wygrecka M, Markart P, Preissner KT. Factor XII Is a novel mitogenic factor for alveolar type II cells in pulmonary fibrosis. Am J Respir Crit Care Med. 2007: A735.
• 59 Ambrus JL, Ambrus CM. Changes in the fibrinolysin system in infantile and adult respiratory distress syndrome (ARDS), caused by trauma and/or septic shock in patients and experimental animals. J Med 1990; 21: 67-84.
• 60 Fourrier F, Chopin C, Goudemand J. et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992; 101: 816-823.
• 61 Owings JT, Bagley M, Gosselin R. et al. Effect of critical injury on plasma antithrombin activity: low antithrombin levels are associated with thromboembolic complications. J Trauma 1996; 41: 396-405.
• 62 Ware LB, Fang X, Matthay MA. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003; 285: L514-L521.
• 63 Kobayashi H, Gabazza EC, Taguchi O. et al. Protein C anticoagulant system in patients with interstitial lung diseases. Am J Respir Crit Care Med 1998; 157: 1850-1854.
• 64 Yasui H, Gabazza EC, Taguchi O. et al. Decreased protein C activation is associated with abnormal collagen turnover in the intraalveolar space of patients with interstitial lung disease. Clin Appl Thromb Hemost 2000; 6: 202-205.
• 65 De Moerloose P, De Benedetti E, Nicod L. et al. Procoagulant activity in bronchoalveolar lavage fluids: No relationship with tissue factor pathway inhibitor activity. Thromb Res 1992; 65: 507-518.
• 66 D’Angelo A, Lockhart MS, D’Angelo SV. et al. Protein S is a cofactor for activated protein C neutralisation of an inhibitor of plasminogen activation released from platelets. Blood 1987; 69: 231-237.
• 67 Esmon CT. Inflammation and activated protein C anticoagulant pathway. Semin Thromb Haemost. 2006 01 49-60.
• 68 Shimizu S, Gabazza EC, Taguchi O. et al. Activated protein C inhibits the expression of platelet-derived growth factor in the lung. Am J Respir Crit Care Med 2003; 167: 1416-1426.
• 69 Eitzman DT, McCoy RD, Zheng X. 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: 232-237.
• 70 Sisson TH, Hanson KE, Subbotina N. et al. Inducible lung-specific urokinase expression reduces fibrosis mortality after lung injury in mice. Am J Physiol 2002; 283: L1023-1032.
• 71 Markart P, Ruppert C, Petri K. et al. Transgenic Mice expressing a surfactant protein-B-urokinasefusion protein in the distal respiratory epithelium show improved survival after bleomycin-induced lung injury. Am J Respir Crit Care Med. 2005: A346.
• 72 Fujimoto H, Gabazza EC, Hataji O. et al. Thrombin- Activatable Fibrinolysis Inhibitor and Protein C Inhibitor in interstitial lung disease. Am J Respir Crit Care Med 2003; 167: 1687-1694.
• 73 Miller DL, Welty-Wolf K, Carraway MS. et al. Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysacharide. Am J Respir Crit Care Med 2002; 26: 650-658.
• 74 Enkhbaatar P, Okajima K, Murakami K. et al. Recombinant tissue factor pathway inhibitor reduces lipopolysacharide- induced pulmonary vascular injury by inhibiting leukocyte activation. Am J Respir Crit Care Med 2000; 162: 1752-1759.
• 75 Abraham E, Reinhart K, Svoboda P. et al. Assessment of the safety of the recombinant tissue factor pathway inhibitor in patients with severe sepsis: A multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit Care Med 2001; 29: 2081-2089.
• 76 Abraham E, Reinhart K, Opal S. et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. J Am Med Assoc 2003; 290: 238-247.
• 77 Hoffmann H, Siebeck M, Spannagl M. et al. Effect of recombinant hirudin, a specific inhibitor of thrombin, on endotoxin-induced intravascular coagulation and acute lung injury in pigs. Am Rev Respir Dis 1990; 142: 782-788.
• 78 Schmidt B, Davis P, La Pointe H. et al. Thrombin inhibitors reduce intrapulmonary accumulation of fibrinogen and procoagulant activity of bronchoalveolar lavage fluid during acute lung injury induced by pulmonary overdistention in newborn piglets. Pediatr Res 1996; 39: 798-804.
• 79 Uchiba M, Okajima K. Antithrombin III (AT III) prevents LPS-induced pulmonary vascular injury: novel biological activity of AT III. Semin Thromb Hemost 1997; 23: 583-590.
• 80 Abubakar K, Schmidt B, Monkman S. et al. Heparin improves gas exchange during experimental acute lung injury in newborn piglets. Am J Respir Crit Care Med 1998; 158: 1620-1625.
• 81 Uchiba M, Okajima K, Murakami K. et al. Attenuation of endotoxin-induced pulmonary vascular injury by antithrombin III. Am J Physiol 1996; 270: L921-L930.
• 82 Guenther A, Luebke N, Ermert M. et al. Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits. Am J Respir Crit Care Med 2003; 168: 1358-1365.
• 83 Howell DC, Goldsack NR, Marshall RP. et al. Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis. Am J Pathol 2001; 159: 1383-1395.
• 84 Baudo F, Caimi TM, De Cataldo F. et al. Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study. Intensive Care Med 1998; 24: 336-342.
• 85 Eisele B, Lamy M, Thijs LG. et al. Antithrombin III in patients with severe sepsis. A randomized, placebocontrolled, double-blind multicenter trial plus a metaanalysis on all randomized, placebo-controlled, doubleblind trials with antithrombin III in severe sepsis. Intensive Care Med 1998; 24: 663-672.
• 86 Warren BL, Eid A, Singer P. et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. J Am Med Assoc 2001; 286: 1869-1878.
• 87 Hoffmann JN, Wiedermann CJ, Juers M. et al. Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin. Thromb Haemost 2006; 95: 850-856.
• 88 Kubo H, Nakayama K, Yanai M. et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005; 128: 1475-1482.
• 89 Murakami K, Okajima K, Uchiba M. et al. Activated protein c prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol 1997; 272: L197-L202.
• 90 Yasui H, Gabazza EC, Tamaki S. et al. Intratracheal administration of activated protein C inhibits bleomycin- induced lung fibrosis in the mouse. Am J Respir Crit Care Med 2001; 163: 1660-1668.
• 91 Bernard GR, Vincent JL, Laterre PF. et al. Efficacy and safety of recombinant human APC in severe sepsis. N Engl J Med 2001; 344: 699-709.
• 92 Abraham E, Laterre PF, Garg R. et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005; 353: 1332-1341.
• 93 Hasegawa N, Kandra TG, Husari AW. et al. The effects of recombinant human thrombomodulin on endotoxin induced multiple system organ failure in rats. Am J Respir Crit Care Med 1996; 153: 1831-1837.
• 94 Uchiba M, Okajima K, Murakami K. et al. Recombinant thrombomodulin prevents endotoxin induced lung injury in rats by inhibiting leukocyte activation. Am J Physiol 1996; 271: L470-L475.
• 95 Hardaway RM, Williams CH, Marvasti M. et al. Prevention of adult respiratory distress syndrome with plasminogen activator in pigs. Crit Care Med 1990; 18: 1413-1418.
• 96 Hart DA, Whidden P, Green F. et al. Partial reversal of established bleomycin-induced pulmonary fibrosis by rh-urokinase in a rat model. Clin Invest Med 1994; 17: 69-76.
• 97 Ikeda T, Hirose N, Koto H. et al. Fibrin deposition and fibrinolysis in the pathogenesis of pulmonary fibrosis. Nihon Kyobu Shikkan Gakkai Zasshi 1989; 27: 448-451.
• 98 Hardaway RM, Harke H, Tyroch AH. et al. Treatment of severe acute respiratory distress syndrome: A final report on a phase I study. Am Surg 2001; 67: 377-382.