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DOI: 10.1055/s-0028-1092878
The Role of Bronchoalveolar Hemostasis in the Pathogenesis of Acute Lung Injury
Publikationsverlauf
Publikationsdatum:
27. Oktober 2008 (online)
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ABSTRACT
Disturbed alveolar fibrin turnover is intrinsic to acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pneumonia and is important to its pathogenesis. Recent studies also suggest disturbed alveolar fibrin turnover to be a feature of ventilator-induced lung injury (VILI). The mechanisms that contribute to alveolar coagulopathy are localized tissue factor–mediated thrombin generation, impaired activity of natural coagulation inhibitors, and depression of bronchoalveolar urokinase plasminogen activator–mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. Administration of anticoagulant agents (including activated protein C, antithrombin, tissue factor–factor VIIa pathway inhibitors, and heparin) and profibrinolytic agents (including plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ALI/ARDS and pneumonia. In this article, we review the involvement of coagulation and fibrinolysis in the pathogenesis of ALI/ARDS pneumonia and VILI and the potential of anticoagulant and profibrinolytic strategies to reverse pulmonary coagulopathy and pulmonary inflammatory responses.
KEYWORDS
Acute lung injury - acute respiratory distress syndrome - coagulation - fibrinolysis
REFERENCES
- 1 Bernard G R, Artigas A, Brigham K L 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
- 2 Davis K A. Ventilator-associated pneumonia: a review. J Intensive Care Med. 2006; 21 211-226
- 3 Dos Santos C C, Slutsky A S. Invited review: mechanisms of ventilator-induced lung injury: a perspective. J Appl Physiol. 2000; 89 1645-1655
- 4 Levi M, Ten C H. Disseminated intravascular coagulation. N Engl J Med. 1999; 341 586-592
- 5 Schultz M J, Haitsma J J, Zhang H, Slutsky A S. Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia—a review. Crit Care Med. 2006; 34 871-877
- 6 Dahlem P, Bos A P, Haitsma J J, Schultz M J, Meijers J C, Lachmann B. Alveolar fibrinolytic capacity suppressed by injurious mechanical ventilation. Intensive Care Med. 2005; 31 724-732
- 7 Dahlem P, Bos A P, Haitsma J J et al.. Mechanical ventilation affects alveolar fibrinolysis in LPS-induced lung injury. Eur Respir J. 2006; 28 992-998
- 8 Welty-Wolf K E, Carraway M S, Ortel T L, Piantadosi C A. Coagulation and inflammation in acute lung injury. Thromb Haemost. 2002; 88 17-25
- 9 Biemond B J, Levi M, Ten C H et al.. Complete inhibition of endotoxin-induced coagulation activation in chimpanzees with a monoclonal Fab fragment against factor VII/VIIa. Thromb Haemost. 1995; 73 223-230
- 10 Levi M, Ten C H, Bauer K A et al.. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest. 1994; 93 114-120
- 11 Levi M, Schultz M J, Rijneveld A W. van der PT. Bronchoalveolar coagulation and fibrinolysis in endotoxemia and pneumonia. Crit Care Med. 2003; 31 S238-S242
- 12 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
- 13 Faust S N, Levin M, Harrison O B et al.. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med. 2001; 345 408-416
- 14 Moore K L, Esmon C T, Esmon N L. Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood. 1989; 73 159-165
- 15 Nawroth P P, Stern D M. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med. 1986; 163 740-745
- 16 Sawdey M S, Loskutoff D J. 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 1346-1353
- 17 Abraham E, Reinhart K, Svoboda P et al.. Assessment of the safety of 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
- 18 Eisele B, Lamy M, Thijs L G et al.. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intensive Care Med. 1998; 24 663-672
- 19 Warren B L, Eid A, Singer P et al.. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001; 286 1869-1878
- 20 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. JAMA. 2003; 290 238-247
- 21 Bernard G R, Vincent J L, Laterre P F et al.. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 344 699-709
- 22 Dellinger R P, Carlet J M, Masur H et al.. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med. 2004; 30 536-555
- 23 Gunther A, Mosavi P, Heinemann S et al.. Alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. Comparison with the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2000; 161 454-462
- 24 Idell S, Gonzalez K, Bradford H et al.. Procoagulant activity in bronchoalveolar lavage in the adult respiratory distress syndrome. Contribution of tissue factor associated with factor VII. Am Rev Respir Dis. 1987; 136 1466-1474
- 25 Idell S, Koenig K B, Fair D S, Martin T R, McLarty J, Maunder R J. Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome. Am J Physiol. 1991; 261 L240-L248
- 26 Fuchs-Buder T, de Moerloose P, Ricou B et al.. Time course of procoagulant activity and D dimer in bronchoalveolar fluid of patients at risk for or with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996; 153 163-167
- 27 Miller D L, Welty-Wolf K, Carraway M S et al.. Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide. Am J Respir Cell Mol Biol. 2002; 26 650-658
- 28 Ware L B, Fang X, Matthay M A. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2003; 285 L514-L521
- 29 Okajima K. Antithrombin prevents endotoxin-induced pulmonary vascular injury by inhibiting leukocyte activation. Blood Coagul Fibrinolysis. 1998; 9(Suppl 2) S25-S37
- 30 de Moerlosse P, De Benedetti E, Nicod L, Vifian C, Reber G. Procoagulant activity in bronchoalveolar fluids: no relationship with tissue factor pathway inhibitor activity. Thromb Res. 1992; 65 507-518
- 31 Idell S. Endothelium and disordered fibrin turnover in the injured lung: newly recognized pathways. Crit Care Med. 2002; 30 S274-S280
- 32 Marshall B C, Sageser D S, Rao N V, Emi M, Hoidal J R. Alveolar epithelial cell plasminogen activator. Characterization and regulation. J Biol Chem. 1990; 265 8198-8204
- 33 Prabhakaran P, Ware L B, White K E, Cross M T, Matthay M A, Olman M A. Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2003; 285 L20-L28
- 34 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
- 35 Chapman H A, Stahl M, Allen C L, Yee R, Fair D S. Regulation of the procoagulant activity within the bronchoalveolar compartment of normal human lung. Am Rev Respir Dis. 1988; 137 1417-1425
- 36 Levi M, van Der P OLL, Ten C H et al.. Differential effects of anti-cytokine treatment on bronchoalveolar hemostasis in endotoxemic chimpanzees. Am J Respir Crit Care Med. 1998; 158 92-98
- 37 Chapman H A, Yang X L, Sailor L Z, Sugarbaker D J. Developmental expression of plasminogen activator inhibitor type 1 by human alveolar macrophages. Possible role in lung injury. J Immunol. 1990; 145 3398-3405
- 38 Boutten A, Dehoux M S, Seta N et al.. Compartmentalized IL-8 and elastase release within the human lung in unilateral pneumonia. Am J Respir Crit Care Med. 1996; 153 336-342
- 39 Dehoux M S, Boutten A, Ostinelli J et al.. Compartmentalized cytokine production within the human lung in unilateral pneumonia. Am J Respir Crit Care Med. 1994; 150 710-716
- 40 Millo J L, Schultz M J, Williams C et al.. Compartmentalization of cytokines and cytokine inhibitors in ventilator-associated pneumonia. Intensive Care Med. 2004; 30 68-74
- 41 Abraham E. Coagulation abnormalities in acute lung injury and sepsis. Am J Respir Cell Mol Biol. 2000; 22 401-404
- 42 Schultz M J, Millo J, Levi M et al.. Local activation of coagulation and inhibition of fibrinolysis in the lung during ventilator associated pneumonia. Thorax. 2004; 59 130-135
- 43 Drake T A, Morrissey J H, Edgington T S. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol. 1989; 134 1087-1097
- 44 Altieri D C. Inflammatory cell participation in coagulation. Semin Cell Biol. 1995; 6 269-274
- 45 Chapman H A. Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration. Curr Opin Cell Biol. 1997; 9 714-724
- 46 Eckle I, Seitz R, Egbring R, Kolb G, Havemann K. Protein C degradation in vitro by neutrophil elastase. Biol Chem Hoppe Seyler. 1991; 372 1007-1013
- 47 Choi G, Schultz M J, Levi M, van der P T, Millo J L, Garrard C S. Protein C in pneumonia. Thorax. 2005; 60 705-706
- 48 Choi G, Wolthuis E K, Bresser P et al.. Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents alveolar coagulation in patients without lung injury. Anesthesiology. 2006; 105 689-695
- 49 van der P T, Levi M, Nick J A, Abraham E. Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans. Am J Respir Crit Care Med. 2005; 171 1125-1128
- 50 Choi G, Hofstra J J, Roelofs J J et al.. Recombinant human activated protein C inhibits local and systemic activation of coagulation without influencing inflammation during Pseudomonas aeruginosa pneumonia in rats. Crit Care Med. 2007; 35 1362-1368
- 51 Choi G, Hofstra J J, Roelofs J J et al.. Antithrombin inhibits bronchoalveolar activation of coagulation and limits lung injury during Streptococcus pneumoniae pneumonia in rats. Crit Care Med. 2008; 36 204-210
- 52 Altemeier W A, Matute-Bello G, Frevert C W et al.. Mechanical ventilation with moderate tidal volumes synergistically increases lung cytokine response to systemic endotoxin. Am J Physiol Lung Cell Mol Physiol. 2004; 287 L533-L542
- 53 Belperio J A, Keane M P, Burdick M D et al.. Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. J Clin Invest. 2002; 110 1703-1716
- 54 Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000; 342 1301-1308
- 55 Ranieri V M, Suter P M, Tortorella C et al.. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1999; 282 54-61
- 56 Wolthuis E K, Choi G, Dessing M C et al.. Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents pulmonary inflammation in patients without preexisting lung injury. Anesthesiology. 2008; 108 46-54
- 57 Haitsma J J, Wolthuis E K, Schultz M J, Levi M, Zhang H, Slutsky A S. Ventilator-induced coagulopathy in experimental Streptococcus pneumoniae pneumonia. Presented at: Annual Meeting of the American Thoracic Society May 20, 2007 San Francisco, CA;
- 58 Coughlin S R. Thrombin signalling and protease-activated receptors. Nature. 2000; 407 258-264
- 59 Levi M, van der P T, Ten C H. Tissue factor in infection and severe inflammation. Semin Thromb Hemost. 2006; 32 33-39
- 60 Camerer E, Gjernes E, Wiiger M, Pringle S, Prydz H. Binding of factor VIIa to tissue factor on keratinocytes induces gene expression. J Biol Chem. 2000; 275 6580-6585
- 61 Ollivier V, Bentolila S, Chabbat J, Hakim J, de Prost D. Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII. Blood. 1998; 91 2698-2703
- 62 Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond). 2005; 109 227-241
- 63 Cunningham M A, Romas P, Hutchinson P, Holdsworth S R, Tipping P G. Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. Blood. 1999; 94 3413-3420
- 64 Johnson K, Choi Y, DeGroot E, Samuels I, Creasey A, Aarden L. Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. J Immunol. 1998; 160 5130-5135
- 65 Johnson K, Aarden L, Choi Y, De G E, Creasey A. The proinflammatory cytokine response to coagulation and endotoxin in whole blood. Blood. 1996; 87 5051-5060
- 66 Sower L E, Froelich C J, Carney D H, Fenton J W, Klimpel G R. Thrombin induces IL-6 production in fibroblasts and epithelial cells. Evidence for the involvement of the seven-transmembrane domain (STD) receptor for alpha-thrombin. J Immunol. 1995; 155 895-901
- 67 Huang J S, Ramamurthy S K, Lin X, Le Breton G C. Cell signalling through thromboxane A2 receptors. Cell Signal. 2004; 16 521-533
- 68 Ruggeri Z M. Platelets in atherothrombosis. Nat Med. 2002; 8 1227-1234
- 69 Goff C D, Corbin R S, Theiss S D et al.. Postinjury thromboxane receptor blockade ameliorates acute lung injury. Ann Thorac Surg. 1997; 64 826-829
- 70 Zarbock A, Singbartl K, Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest. 2006; 116 3211-3219
- 71 Pitchford S C, Momi S, Giannini S et al.. Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation. Blood. 2005; 105 2074-2081
- 72 Carvalho-Tavares J, Hickey M J, Hutchison J, Michaud J, Sutcliffe I T, Kubes P. A role for platelets and endothelial selectins in tumor necrosis factor-alpha-induced leukocyte recruitment in the brain microvasculature. Circ Res. 2000; 87 1141-1148
- 73 Drew A F, Liu H, Davidson J M, Daugherty C C, Degen J L. Wound-healing defects in mice lacking fibrinogen. Blood. 2001; 97 3691-3698
- 74 Perez R L, Ritzenthaler J D, Roman J. Transcriptional regulation of the interleukin-1beta promoter via fibrinogen engagement of the CD18 integrin receptor. Am J Respir Cell Mol Biol. 1999; 20 1059-1066
- 75 Roman J, Ritzenthaler J D, Perez R L, Roser S L. Differential modes of regulation of interleukin-1beta expression by extracellular matrices. Immunology. 1999; 98 228-237
- 76 Sitrin R G, Pan P M, Srikanth S, Todd III R F. Fibrinogen activates NF-kappa B transcription factors in mononuclear phagocytes. J Immunol. 1998; 161 1462-1470
- 77 Idell S, James K K, Levin E G 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
- 78 Seeger W, Stohr G, Wolf H R, Neuhof H. Alteration of surfactant function due to protein leakage: special interaction with fibrin monomer. J Appl Physiol. 1985; 58 326-338
- 79 Seeger W, Gunther A, Thede C. Differential sensitivity to fibrinogen inhibition of SP-C- vs. SP-B-based surfactants. Am J Physiol. 1992; 262 L286-L291
- 80 Esmon C T. The protein C pathway. Chest. 2003; 124 26S-32S
- 81 Yasui H, Gabazza E C, 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
- 82 Murakami K, Okajima K, Uchiba M et al.. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood. 1996; 87 642-647
- 83 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
- 84 Slofstra S H, Groot A P, Maris N A, Reitsma P H, Cate H T, Spek C A. Inhalation of activated protein C inhibits endotoxin-induced pulmonary inflammation in mice independent of neutrophil recruitment. Br J Pharmacol. 2006; 149 740-746
- 85a Kotanidou A, Loutrari H, Papadomichelakis E et al.. Inhaled activated protein C attenuates lung injury induced by aerosolized endotoxin in mice. Vascul Pharmacol. 2006; 45 134-140
- 85b Liu K D, Levitt J, Zhuo H et al.. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med. 2008; 178 618-623
- 86 Welty-Wolf K E, Carraway M S, Miller D L et al.. Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons. Am J Respir Crit Care Med. 2001; 164 1988-1996
- 87 Welty-Wolf K E, Carraway M S, Ortel T L et al.. Blockade of tissue factor-factor X binding attenuates sepsis-induced respiratory and renal failure. Am J Physiol Lung Cell Mol Physiol. 2006; 290 L21-L31
- 88 Enkhbaatar P, Okajima K, Uchiba M, Isobe H, Okabe H. Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide. Thromb Haemost. 2001; 86 1573-1577
- 89 Creasey A A, Chang A C, Feigen L, Wun T C, Taylor Jr F B, Hinshaw L B. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest. 1993; 91 2850-2860
- 90 Carraway M S, Welty-Wolf K E, Miller D L et al.. Blockade of tissue factor: treatment for organ injury in established sepsis. Am J Respir Crit Care Med. 2003; 167 1200-1209
- 91 Opal S M, Palardy J E, Parejo N A, Creasey A A. The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis. Crit Care Med. 2001; 29 13-17
- 92 Enkhbaatar P, Okajima K, Murakami K et al.. Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation. Am J Respir Crit Care Med. 2000; 162 1752-1759
- 93 Horie S, Ishii H, Kazama M. Heparin-like glycosaminoglycan is a receptor for antithrombin III-dependent but not for thrombin-dependent prostacyclin production in human endothelial cells. Thromb Res. 1990; 59 895-904
- 94 Yamauchi T, Umeda F, Inoguchi T, Nawata H. Antithrombin III stimulates prostacyclin production by cultured aortic endothelial cells. Biochem Biophys Res Commun. 1989; 163 1404-1411
- 95 Oelschlager C, Romisch J, Staubitz A et al.. Antithrombin III inhibits nuclear factor kappaB activation in human monocytes and vascular endothelial cells. Blood. 2002; 99 4015-4020
- 96 Harada N, Okajima K, Kushimoto S, Isobe H, Tanaka K. Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. Blood. 1999; 93 157-164
- 97 Kainoh M, Imai R, Umetsu T, Hattori M, Nishio S. Prostacyclin and beraprost sodium as suppressors of activated rat polymorphonuclear leukocytes. Biochem Pharmacol. 1990; 39 477-484
- 98 Kaneider N C, Egger P, Dunzendorfer S, Wiedermann C J. Syndecan-4 as antithrombin receptor of human neutrophils. Biochem Biophys Res Commun. 2001; 287 42-46
- 99 Ostrovsky L, Woodman R C, Payne D, Teoh D, Kubes P. Antithrombin III prevents and rapidly reverses leukocyte recruitment in ischemia/reperfusion. Circulation. 1997; 96 2302-2310
- 100 Duensing T D, Wing J S, van Putten J P. Sulfated polysaccharide-directed recruitment of mammalian host proteins: a novel strategy in microbial pathogenesis. Infect Immun. 1999; 67 4463-4468
- 101 Kipnis E, Guery B P, Tournoys A et al.. Massive alveolar thrombin activation in Pseudomonas aeruginosa-induced acute lung injury. Shock. 2004; 21 444-451
- 102 Hochart H, Jenkins P V, Smith O P, White B. Low-molecular weight and unfractionated heparins induce a downregulation of inflammation: decreased levels of proinflammatory cytokines and nuclear factor-kappaB in LPS-stimulated human monocytes. Br J Haematol. 2006; 133 62-67
- 103 Lever R, Page C P. Novel drug development opportunities for heparin. Nat Rev Drug Discov. 2002; 1 140-148
- 104 Uchiba M, Okajima K, Murakami K, Okabe H, Takatsuki K. Attenuation of endotoxin-induced pulmonary vascular injury by antithrombin III. Am J Physiol. 1996; 270 L921-L930
- 105 Schiffer E R, Reber G, de M P, Morel D R. Evaluation of unfractionated heparin and recombinant hirudin on survival in a sustained ovine endotoxin shock model. Crit Care Med. 2002; 30 2689-2699
- 106 Darien B J, Fareed J, Centgraf K S et al.. Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model. Shock. 1998; 9 274-281
- 107 Slofstra S H, van't Veer C, Buurman W A, Reitsma P H, ten Cate H, Spek C A. Low molecular weight heparin attenuates multiple organ failure in a murine model of disseminated intravascular coagulation. Crit Care Med. 2005; 33 1365-1370
- 108 Cox Jr C S, Zwischenberger J B, Traber D L, Traber L D, Haque A K, Herndon D N. Heparin improves oxygenation and minimizes barotrauma after severe smoke inhalation in an ovine model. Surg Gynecol Obstet. 1993; 176 339-349
- 109 Murakami K, McGuire R, Cox R A et al.. Heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep. Shock. 2002; 18 236-241
- 110 Stringer K A, Lindenfeld J, Repine A J, Cohen Z, Repine J E. Tissue plasminogen activator (tPA) inhibits human neutrophil superoxide anion production in vitro. Inflammation. 1997; 21 27-34
- 111 Abraham E, Gyetko M R, Kuhn K et al.. Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation. J Immunol. 2003; 170 5644-5651
- 112 Hardaway R M, Williams C H, Marvasti M et al.. Prevention of adult respiratory distress syndrome with plasminogen activator in pigs. Crit Care Med. 1990; 18 1413-1418
- 113 Stringer K A, Hybertson B M, Cho O J, Cohen Z, Repine J E. Tissue plasminogen activator (tPA) inhibits interleukin-1 induced acute lung leak. Free Radic Biol Med. 1998; 25 184-188
- 114 Choi G, Vlaar A P, Schouten M et al.. Natural anticoagulants limit LPS-induced pulmonary coagulation but not inflammation. Eur Respir J. 2007; 30 423-428
- 115 Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med. 2003; 31 S213-S220
- 116 MacLaren R, Stringer K A. Emerging role of anticoagulants and fibrinolytics in the treatment of acute respiratory distress syndrome. Pharmacotherapy. 2007; 27 860-873
- 117 Ware L B, Bastarache J A, Wang L. Coagulation and fibrinolysis in human acute lung injury—new therapeutic targets?. Keio J Med. 2005; 54 142-149
- 118 Ware L B, Camerer E, Welty-Wolf K, Schultz M J, Matthay M A. Bench to bedside: targeting coagulation and fibrinolysis in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2006; 291 L307-L311
- 119 Laterre P F, Garber G, Levy H et al.. Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study. Crit Care Med. 2005; 33 952-961
- 120 Lahteenmaki K, Kuusela P, Korhonen T K. Bacterial plasminogen activators and receptors. FEMS Microbiol Rev. 2001; 25 531-552
- 121 Robriquet L, Collet F, Tournoys A et al.. Intravenous administration of activated protein C in Pseudomonas-induced lung injury: impact on lung fluid balance and the inflammatory response. Respir Res. 2006; 7 41
- 122 ISRCTN52566874 . Activated protein C versus placebo in the treatment of inflammatory or infectious ALI/ARDS (INFALI): a pathophysiological study on pulmonary microvascular permeability, apoptosis, inflammation and coagulation. 2007;
- 123 Seeger W, Hubel J, Klapettek K et al.. Procoagulant activity in bronchoalveolar lavage of severely traumatized patients–relation to the development of acute respiratory distress. Thromb Res. 1991; 61 53-64
- 124 Gunther A, Kalinowski M, Elssner A, Seeger W. Clot-embedded natural surfactant: kinetics of fibrinolysis and surface activity. Am J Physiol. 1994; 267 L618-L624
Jorrit–Jan H HofstraM.D.
Department of Intensive Care Medicine, Academic Medical Center
University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
eMail: j.j.hofstra@amc.uva.nl