Coagulation and Inflammation in Acute Lung Injury

 

 Buy Article Permissions and Reprints

Summary

The acute respiratory distress syndrome (ARDS) is a severe lung injury in patients with sepsis and other acute inflammatory insults, which is characterized by fibrin deposition in the pulmonary parenchyma, vasculature, and airspaces. Recent evidence suggests that progressive ARDS is closely linked to activation of inflammation and coagulation. Coagulation becomes activated by circulating endotoxin or bacteria, and a procoagulant state develops in the vascular and the alveolar compartments of the lung. This state is Tissue Factor (TF)-dependent and associated with increased elaboration of inflammatory cytokines. A similar procoagulant state is found in bronchoalveolar lavage of patients with ARDS, suggesting that extravascular coagulation contributes to lung inflammation. TF and other coagulation proteins, including Factor Xa, thrombin, and fibrin, also contribute to the pathogenesis of acute lung injury through multi-level interactions with inflammatory effectors, in which these proteins coordinately act as regulators of tissue injury responses. Each coagulation protein has direct and independent effects on inflammatory events that influences lung injury through changes in cytokine elaboration, inflammatory cell migration and activation, surfactant function, and repair mechanisms. New interventional strategies directed at procoagulant activity highlight the importance of the coagulation system to acute lung injury and suggest that blockade of initiation of coagulation may have therapeutic benefit in patients with ARDS.

• References

• 1 Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 02: 319-23.
  PubMedGoogle Scholar
• 2 Bachofen M, Weibel ER. Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med 1982; 03: 35-56.
  PubMedGoogle Scholar
• 3 Idell S. Extravascular coagulation and fibrin deposition in acute lung injury. New Horiz 1994; 02: 566-74.
  PubMedGoogle Scholar
• 4 Kaplan RL, Sahn SA, Petty TL. Incidence and outcome of the respiratory distress syndrome in gram-negative sepsis. Arch Int Med 1979; 139: 867-9.
  CrossrefPubMedGoogle Scholar
• 5 Fein AM, Lippmann M, Holtzman H, Eliraz A, Goldberg SK. The risk factors, incidence, and prognosis of ARDS following septicemia. Chest 1983; 83: 40-2.
  CrossrefPubMedGoogle Scholar
• 6 Kreger BE, Craven DE, McCabe WR. Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med 1980; 68: 344-55.
  CrossrefPubMedGoogle Scholar
• 7 Ware LB, Matthay MA. The acute respiratory distress syndrome. N Eng J Med 2000; 342: 1334-49.
  CrossrefPubMedGoogle Scholar
• 8 Fujishima S, Aikawa N. Neutrophil-mediated tissue injury and its modulation. Int Care Med 1995; 21: 277-85.
  CrossrefPubMedGoogle Scholar
• 9 Goodman RB, Strieter RM, Steinberg KP, Milberg JA, Martin DP, Maunder RJ, Kunkel SL, Walz A, Hudson LD, Martin TR. Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1996; 154: 602-11.
  CrossrefPubMedGoogle Scholar
• 10 Abraham E. Why immunomodulatory therapies have not worked in sepsis. Int Care Med 1999; 25: 556-66.
  CrossrefPubMedGoogle Scholar
• 11 McIntyre Jr RC, Pulido EJ, Bensard DD, Shames BD, Abraham E. Thirty years of clinical trials in acute respiratory distress syndrome. Crit Care Med 2000; 28: 3314-31.
  CrossrefPubMedGoogle Scholar
• 12 van Deventer SJ, Buller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76: 2520-26.
  PubMedGoogle Scholar
• 13 Biemond BJ, Levi M, ten Cate H, Soulde HR, Morris LD, Foster DL, Bogowitz CA, van der Poll T, Buller HR, ten Cate JW. Complete inhibition of endotoxin-induced coagulation activation in chimpanzees with a monoclonal Fab fragment against factor VII/VIIa. Thromb Hemost 1995; 73: 223-30.
  Article in Thieme ConnectPubMedGoogle Scholar
• 14 Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Buller HR, van Deventer SJH, Hack CE, ten Cate JW, Rosenberg RD. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxyphylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994; 93: 114-20.
  CrossrefPubMedGoogle Scholar
• 15 Franco RF, de Jonge E, Dekkers PEP, Timmerman JJ, Spek CA, van Deventer JH, van Deursen P, van Kerkhoff L, van Gemen B, ten Cate H, van der Poll T, Reitsma PH. The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation. Blood 2000; 96: 554-59.
  PubMedGoogle Scholar
• 16 van der Poll T, Levi M, Hack CE, ten Cate H, van Deventer SJH, Eerenberg AJM, de Groot ELR, Jansen J, Gallati H, Buller HR. Elimination of IL-6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994; 179: 1253-9.
  CrossrefPubMedGoogle Scholar
• 17 van der Poll T, Levi M, van Deventer SJH, ten Cate H, Haagmans BL, Biemond BJ, Buller HR, Hack CE, ten Cate JW. Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. Blood 1994; 83: 446-51.
  PubMedGoogle Scholar
• 18 Levi M, van der Poll T, ten Cate H, van Deventer SJH. The cytokinemediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. J Clin Invest 1977; 27: 3-9.
  PubMedGoogle Scholar
• 19 Meduri GU, Kohler G, Headley S, Tolley E, Stentz F, Postlethwaite A. Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest 1995; 108: 1303-14.
  CrossrefPubMedGoogle Scholar
• 20 Jansen PM, Boermeester MA, Fischer E, de Jong IW, van der Poll T, Moldawer LL, Hack CE, Lowry SF. Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretory-type phospholipase A2 in sepsis: studies in nonhuman primates after interleukin-1 alpha administration and during lethal bacteremia. Blood 1995; 86: 1027-34.
  PubMedGoogle Scholar
• 21 van der Poll T, Levi M, Buller HR, van Deventer SJ, de Boer JP, Hack CE, ten Cate JW. Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 1991; 174: 729-32.
  CrossrefPubMedGoogle Scholar
• 22 Hinshaw LB, Tekamp-Olson P, Chang ACK. Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF). Circ Shock 1990; 30: 279-92.
  PubMedGoogle Scholar
• 23 Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, Marey A, Lestavel P. Septic shock, multiple organ failure and disseminated intravascular coagulation: Compared patterns of antithrombin III, protein C and protein S deficiencies. Chest 1992; 101: 816-21.
  CrossrefPubMedGoogle Scholar
• 24 Jordan RE, Kilpatrick J, Nelson RM. Heparin promotes the inactivation of antithrombin by neutrophil elastase. Science 1987; 237 4816 777-9.
  CrossrefPubMedGoogle Scholar
• 25 Esmon C. The protein C pathway. Crit Care Med 2000; 28: S44-8.
  CrossrefPubMedGoogle Scholar
• 26 Taylor Jr FB, Chang A, Esmon CT, D’Angelo A, Vigano-D’Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918-25.
  CrossrefPubMedGoogle Scholar
• 27 Taylor FB, Emerson TE, Jordan R, Chang AK, Blick KE. Antithrombin-III prevents the lethal effects of Eschericia coli infusion in baboons. Circ Shock 1988; 26: 227-35.
  PubMedGoogle Scholar
• 28 Bajaj MS, Bajaj SP. Tissue factor pathway inhibitor: potential therapeutic applications. Thromb Haemost 1997; 78: 471-7.
  Article in Thieme ConnectPubMedGoogle Scholar
• 29 Okajima K, Sakamoto Y, Uchiba M. Heterogeneity in the incidence and clinical manifestations of disseminated intravascular coagulation: a study of 204 cases. Am J Hematol 2000; 65: 215-22.
  CrossrefPubMedGoogle Scholar
• 30 Hara S, Asada Y, Hatakeyama K, Marutsuka K, Sato Y, Kisanuki A, Sumiyoshi A. Expression of tissue factor and tissue factor pathway inhibitor in rat lungs with lipopolysaccharide-induced disseminated intravascular coagulation. Lab Invest 1997; 77: 581-9.
  PubMedGoogle Scholar
• 31 Giebler R, Schmidt U, Koch S, Peters J, Scherer R. Combined antithrombin III and C1-esterase inhibitor treatment decreases intravascular fibrin deposition and attenuates cardiorespiratory impairment in rabbits exposed to Escherichia coli endotoxin. Crit Care Med 1999; 27: 597-604.
  CrossrefPubMedGoogle Scholar
• 32 Bernard GR, Vincent J-L, Laterre P-F, LaRosa SP, Dhainaut J-F, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher Jr CJ. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
  CrossrefPubMedGoogle Scholar
• 33 Hoffman JN, Faist E. Coagulation inhibitor replacement during sepsis: Useless?. Crit Care Med 2001; 28: S74-6.
  PubMedGoogle Scholar
• 34 Levi M, van der Poll T, ten Cate H, Kuipers B, Biemond BJ, Jansen HM, ten Cate JW. Differential effects of anti-cytokine treatment on bronchoalveolar hemostasis in endotoxemic chimpanzees. Am J Resp Crit Care Med 1998; 158: 92-8.
  CrossrefPubMedGoogle Scholar
• 35 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
• 36 Idell S, Koenig KB, Fair DS, Martin TR, McLarty J, Maunder RJ. Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome. Am J Phys 1991; 261: L240-8.
  PubMedGoogle Scholar
• 37 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
• 38 Drake TA, Morrissey JH, Edginton TS. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Path 1989; 134: 1087-97.
  PubMedGoogle Scholar
• 39 McGee MP, Rothberger H. Tissue factor in bronchoalveolar lavage fluids. Evidence for an alveolar macrophage source. Am Rev Respir Dis 1985; 131: 331-6.
  PubMedGoogle Scholar
• 40 Tipping PG, Erlich JH, Apostopoulos J, Mackman N, Loskutoff D, Holdsworth SR. Glomerular tissue factor expression in crescentic glomerulonephritis. Correlations between antigen, activity, and mRNA. Am J Path 1995; 147: 1736-48.
  PubMedGoogle Scholar
• 41 Oeth P, Parry GC, Mackman N. Regulation of the tissue factor gene in human monocytic cells. Role of AP-1, NF-kappa B/Rel, and Sp1 proteins in uninduced and lipopolysaccharide-induced expression. Arterioscler Thromb Vasc Biol 1997; 17: 365-74.
  CrossrefPubMedGoogle Scholar
• 42 Spragg RG, Smith RM. Biology of Acute Lung Injury. In: The Lung: Scientific Foundations. Crystal RG, West JB. Eds. New York: Raven Press; 1991: 2003-17.
  Google Scholar
• 43 Altieri DC. Inflammatory cell participation in coagulation. Sem Cell Biol 1995; 06: 269-74.
  CrossrefPubMedGoogle Scholar
• 44 Chapman HA. Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration. Curr Opin Cell Biol 1997; 09: 714-24.
  CrossrefPubMedGoogle Scholar
• 45 Drew AF, Liu H, Davidson JM, Daugherty CC, Degen JL. Wound-healing defects in mice lacking fibrinogen. Blood 2001; 97: 3691-8.
  CrossrefPubMedGoogle Scholar
• 46 Sitrin RG, Pan PM, Srikanth S, Todd RF. Fibrinogen activates NF-kappa B transcription factors in mononuclear phagocytes. J Immunol 1998; 161: 1462-70.
  CrossrefPubMedGoogle Scholar
• 47 Perez RL, Ritzenthaler JD, Roman J. Transcriptional regulation of the interleukin-1beta promoter via fibrinogen engagement of the CD18 integrin receptor. Am J Resp Cell Mol Bio 1999; 20: 1059-66.
  PubMedGoogle Scholar
• 48 Seeger W, Stohr G, Wolf HR, Neuhof H. Alteration of surfactant function due to protein leakage: special interaction with fibrin monomer. J App Phys 1985; 58: 326-38.
  CrossrefPubMedGoogle Scholar
• 49 Seeger W, Grube C, Gunther A. Proteolytic cleavage of finbrinogen: amplification of its surfactant inhibitory capacity. Am J Respir Cell Mol Biol 1993; 09: 239-47.
  CrossrefPubMedGoogle Scholar
• 50 Taylor Jr FB, Abrams ME. The effect of surface-active lipoprotein on clotting, fibrinolysis, and of fibrinogen on the surface tension of surface-active lipoprotein. Am J Med 1966; 40: 340-50.
  PubMedGoogle Scholar
• 51 Barazzone C, Beline D, Piqueet PF, Vasalli JD, Sappino AP. Plasminogen activator inhibitor-1 in acute hyperoxic mouse lung injury. J Clin Invest 1996; 98: 2666-73.
  CrossrefPubMedGoogle Scholar
• 52 Eitzman DT, McCoooy 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 gene. J Clin Invest 1996; 97: 232-7.
  CrossrefPubMedGoogle Scholar
• 53 Welty-Wolf KE, Carraway MS, Miller DL, Ortel TL, Ezban M, Ghio AJ, Idell S, Piantadosi CA. Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons. Am J Resp Crit Care Med 2001; 164 (10 Pt 1) 1988-96.
  CrossrefPubMedGoogle Scholar
• 54 Idell S, James KK, Gillies 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 Path 1989; 135: 387-99.
  PubMedGoogle Scholar
• 55 Sitrin RG, Brubaker PG, Fantone JC. Tissue fibrin deposition during acute lung injury in rabbits and its relationship to local expression of procoagulant and fibrinolytic activities. Am Rev Resp Dis 1987; 135: 930-6.
  PubMedGoogle Scholar
• 56 McDonald JA. The yin and yang of fibrin in the airways. New Eng J Med 1990; 322: 929-31.
  CrossrefPubMedGoogle Scholar
• 57 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
• 58 Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U.S.A 1990; 87: 6934-8.
  CrossrefPubMedGoogle Scholar
• 59 Rottingen JA, Enden T, Camerer E, Iversen JG, Prydz H. Binding of human factor VIIa to tissue factor induces cytosolic Ca2+ signals in J82 cells, transfected COS-1 cells, Madin-Darby canine kidney cells and in human endothelial cells induced to synthesize tissue factor. J Biol Chem 1995; 270: 4650-60.
  CrossrefPubMedGoogle Scholar
• 60 Camerer E, Rottingen JA, Iversen JG, Prydz H. Coagulation factors VII and X induce Ca2+ oscillations in Madin-Darby canine kidney cells only when proteolytically active. J Biol Chem 1996; 271: 29034-42.
  CrossrefPubMedGoogle Scholar
• 61 Peterson LC, Freskgard P-O, Ezban M. Tissue factor-dependent factor VIIa signaling. Trends Cardiovasc Med 2000; 10: 47-52.
  CrossrefPubMedGoogle Scholar
• 62 Ott I, Fischer EG, Miyagi Y, Mueller BM, Ruf W. A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J Cell Bio 1998; 140: 1241-53.
  CrossrefPubMedGoogle Scholar
• 63 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: 6580-5.
  CrossrefPubMedGoogle Scholar
• 64 Sørensen BB, Freskgård P, Nielsen LS, Vijaya L, Rao M, Ezban M, Petersen LC. Factor VIIa-induced p44/42 mitogen-activated protein kinase activation requires the proteolytic activity of factor VIIa and is independent of the tissue factor cytoplasmic domain. J Biol Chem 1999; 274: 21349-54.
  CrossrefPubMedGoogle Scholar
• 65 Poulson PK, Jacobsen N, Sorensen BB, Bergenhem NCH, Kelly JD, Foster DC, Thastrup O, Ezban M, Petersen LC. Signal transduction via the mitogen-activated protein kinase pathway induced by binding of coagulation factor FVIIa to tissue factor. J Biol Chem 1998; 273: 6228-32.
  CrossrefPubMedGoogle Scholar
• 66 Neumann F-J, Ott I, Marx N, Luther T, Kenngott S, Gawaz M, Kotsch M, Schomig A. Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity. Arterioscler Thromb Vasc Biol 1997; 17: 3399-405.
  CrossrefPubMedGoogle Scholar
• 67 Pendurthi UR, Alok D, Rao LV. Binding of factor VIIa to tissue factor induces alterations in gene expression in human fibroblast cells: upregulation of poly(A) polymerase. Proc Nat Acad Sci USA 1997; 94: 12598-603.
  CrossrefPubMedGoogle Scholar
• 68 Jackson RJ, Standard N. Do the poly(A) tail and 3’ untranslated region control mRNA translation?. Cell 1990; 62: 15-24.
  CrossrefPubMedGoogle Scholar
• 69 Camerer E, Huang W, Coughlin SR. Tissue factor-and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Nat Acad Sci 2000; 97: 5255-60.
  CrossrefPubMedGoogle Scholar
• 70 Cunningham MA, Romas P, Hutchinson P, Holdsworth SR, Tipping PG. Tissue factor and factor VIIa receptor/ligand interactions induce proinflamatory effects in macrophages. Hem Thromb Vasc Bio 1999; 94: 3413-20.
  PubMedGoogle Scholar
• 71 Taniguchi T, Kakkar AK, Tuddenham EG, Williamson RC, Lemoine NR. Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer. Cancer Res 1998; 58: 4461-7.
  PubMedGoogle Scholar
• 72 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
• 73 Ollivier V, Bentolilq 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: 2698-703.
  PubMedGoogle Scholar
• 74 Abe K, Shoji M, Chen J, Bierhaus A, Danave I, Micko C, Casper K, Dillehay DL, Nawroth PP, Rickles FR. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci USA 1999; 96: 8663-8.
  CrossrefPubMedGoogle Scholar
• 75 Thomas KA. Vascular endothelial growth factor, a potent and selective angiogenic agent. J Biol Chem 1996; 271: 603-6.
  CrossrefPubMedGoogle Scholar
• 76 Ferrara N, Davis-Smith T. The biology of vascular endothelial growth factor. Endo Rev 1997; 18: 4-24.
  CrossrefPubMedGoogle Scholar
• 77 Kaner RJ, Ladetto JV, Singh R, Fukuda N, Matthay MA, Crystal RG. Lung over-expression of the vascular endothelial growth factor gene induces pulmonary edema. Am J Resp Cell Mol Biol 2000; 22: 657-64.
  CrossrefPubMedGoogle Scholar
• 78 Stanokova J, Rola-Pleszczynski M, D’Orleans-Just P. Endothelin 1 and thrombin synergistically stimulate IL-6 mRNA expression and protein production in human umbilical vein endothelial cells. J Cardiovasc Pharm 1995; 26: S505-7.
  CrossrefPubMedGoogle Scholar
• 79 Hou L, Ravenall S, Macey MG, Harriott P, Kapas S, Howells GL. Protease-activated receptors and their role in IL-6 and NF-IL-6 expression in human gingival fibroblasts. J Peridon Res 1998; 33: 205-11.
  PubMedGoogle Scholar
• 80 Shin H, Kitajima I, Nakajima T, Shao Q, Tokioka T, Takasaki I, Hanyu N, Kubo T, Maruyama I. Thrombin receptor mediated signals induce expressions of interleukin 6 and granulocyte colony stimulating factor via NF-kappa B activation in synovial fibroblasts. Ann Rheum Dis 1999; 58: 55-60.
  CrossrefPubMedGoogle Scholar
• 81 Riewald M, Kravchenko VV, Petrovan RJ, O’Brien PJ, Brass LF, Ulevitch RJ, Ruf W. Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1. Blood 2001; 97: 3109-16.
  CrossrefPubMedGoogle Scholar
• 82 Cirino G, Cicala C, Bucci M, Sorrentino L, Ambrosini G, DeDominicis G, Altieri DC. Factor Xa as an interface between coagulation and inflammation. Molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo. J Clin Invest 1997; 99: 2446-51.
  CrossrefPubMedGoogle Scholar
• 83 Nicholson AC, Nachman RL, Altieri DC, Summers BD, Ruf W, Edgington TS, Hajjar DP. Effector cell protease receptor 1 is a vascular receptor for coagulation factor Xa. J Biol Chem 1996; 271: 28407-13.
  CrossrefPubMedGoogle Scholar
• 84 Herbert J-M, Bono F, Herault J-P, Avril C, Dol F, Mares A, Schaeffer P. Effector protease receptor 1 mediates the mitogenic activity of factor Xa for vascular smooth muscle cells in vitro and in vivo. J Clin Invest 1998; 101: 993-1000.
  CrossrefPubMedGoogle Scholar
• 85 Esmon CT. Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?. Blood 2000; 95: 1113-6.
  PubMedGoogle Scholar
• 86 Camerer E, Rottingen JA, Gjernes E, Larsen K, Skartlien AH, Iverson JG, Prydz H. Coagulation factors VIIa and Xa induce cell signaling leading to up-regulation of the egr-1 gene. J Biol Chem 1999; 274: 32225-33.
  CrossrefPubMedGoogle Scholar
• 87 Duchosal MA, Rothermal AL, McConahey PJ, Dixon FJ, Altieri DC. In vivo immunosuppression by targeting a novel protease receptor. Nature 1996; 380: 352-6.
  CrossrefPubMedGoogle Scholar
• 88 Coughlin SR. Thrombin signaling and protease-activated receptors. Nature 2000; 407: 258-64.
  CrossrefPubMedGoogle Scholar
• 89 Lorant DE, Topham MK, Whatley RE, McEver RP, McIntyre TM, Prescott SM, Zimmerman GA. Inflammatory roles of P-Selectin. J Clin Invest 1993; 92: 559-70.
  CrossrefPubMedGoogle Scholar
• 90 Grinnell BW, Joyce D. Recombinant human activated protein C: A system modulator of vascular function for treatment of severe sepsis. Crit Care Med 2001; 29: S53-61.
  CrossrefPubMedGoogle Scholar
• 91 Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001; 276: 11199-203.
  CrossrefPubMedGoogle Scholar
• 92 Laszik Z, Mitro A, Taylor Jr FB, Ferrell G, Esmon CT. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation 1997; 96: 3633-40.
  CrossrefPubMedGoogle Scholar
• 93 Lindahl AK, Jacobsen PB, Sandset PM, Abildgaard U. Tissue factor pathway inhibitor with high anticoagulant activity is expressed in postheparin plasma and in plasma from cancer patients. Blood Coagul Fibrinolysis 1991; 02: 713-21.
  CrossrefPubMedGoogle Scholar
• 94 Sabharwal AK, Bajaj SP, Ameri A, Tricomi SM, Hyers TM, Dahms TE, Taylor Jr FB, Bajaj MS. Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory distress syndrome and in a primate model of sepsis. Am J Resp Crit Care Med 1995; 151: 758-67.
  CrossrefPubMedGoogle Scholar
• 95 Enkhbaatar P, Okajima K, Murakami K, Uchiba M, Okabe H, Okabe K, Yamaguchi Y. Recombinant tissue factor pathway inhibitor reduced lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation. Am J Respir Crit Care Med 2000; 162: 1752-9.
  CrossrefPubMedGoogle Scholar
• 96 Opal SM, Palardy JE, Parejo NA, Creasey AA. The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis. Crit Care Med 2001; 29: 13-7.
  CrossrefPubMedGoogle Scholar
• 97 Kainoh M, Imai R, Umetsu T, Hattori M, Nishio S. Prostacyclin and beraprost sodium as suppressors of activated rat polymorphnuclear leukocytes. Biochem Pharmacol 1990; 39: 477-84.
  CrossrefPubMedGoogle Scholar
• 98 Balk R, Emerson TFourrier, Kruse JA, Mammen EF, Schuster HP, Vinazzer H. Therapeutic use of antithrombin concentrate in sepsis. Semin Thromb Haemost 1998; 24: 183-94.
  Article in Thieme ConnectPubMedGoogle Scholar
• 99 Dscheitzig T, Alexiou K, Laule M, Becker R, Schror K, Baumann G, Brunner F, Stangl K. Stimulation of pulmonary big endothelin-1 and endothelin-1 by antithrombin III: A rationale for combined application of antithrombin III and endothelin antagonists in sepsis-related acute respiratory distress syndrome?. Crit Care Med 2000; 28: 2445-9.
  CrossrefPubMedGoogle Scholar
• 100 Taylor FB, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, Blick K, Edgington TS, Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33: 127-34.
  PubMedGoogle Scholar
• 101 Creasey AA, Chang ACK, Feigen L, Wun T-C, Taylor Jr FB, Hinshaw LB. Tissue factor pathway inhibitor reduces mortality from Eschericia coli septic shock. J Clin Invest 1993; 91: 2850-6.
  CrossrefPubMedGoogle Scholar
• 102 Taylor FB, Chang AC, Peer G, Li A, Ezban M, Hedner U. Active site inhibited Factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Eschericia coli. Blood 1998; 91: 1609-15.
  PubMedGoogle Scholar
• 103 Minnema MC, Chang ACK, Jansen PM, Lubbers YTP, Pratt BM, Whittaker G, Taylor FB, Hack CE, Friedman B. Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Eschericia coli . Blood 2000; 95: 1117-23.
  PubMedGoogle Scholar
• 104 Taylor Jr FB, Chang ACK, Peer G, Mather T, Blick K, Catlett R, Lockhart MS, Esmon CT. DEGR-Factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage. Blood 1991; 78: 362-8.
  PubMedGoogle Scholar
• 105 de Jonge E, Dekkers PEP, Creasey AA, Hack CE, Paulson SK, Karim A, Kesecioglu J, Levi M, van Deventer SJH, van der Poll T. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 2000; 95: 1124-9.
  PubMedGoogle Scholar
• 106 Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke H-O, Heinrichs H, Schindel F, Juers M, Bone R, Opal S. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286: 1869-78.
  CrossrefPubMedGoogle Scholar
• 107 Horgan MJ, Fenton II JW, Malik AB. Alpha-thrombin-induced pulmonary vasoconstriction. J App Physiol 1987; 63: 1993-2000.
  CrossrefPubMedGoogle Scholar
• 108 Hoffman H, Siebeck M, Spannagl M, Weis M, Geiger R, Jochum M, Fritz H. 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: 782-8.
  CrossrefPubMedGoogle Scholar
• 109 Abraham E. Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis. Crit Care Med 2000; 28: S31-3.
  CrossrefPubMedGoogle Scholar