Pathophysiology of Acute Lung Injury

 

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ABSTRACT

The acute respiratory distress syndrome (ARDS) is a life-threatening syndrome that may occur in any patient without any predisposition and that is mostly triggered by underlying processes such as sepsis, pneumonia, trauma, multiple transfusions, and pancreatitis. ARDS is defined by (1) acute onset, (2) bilateral infiltrates in chest x-rays, (3) absence of left ventricular failure, and (4) severe arterial hypoxemia with a PaO₂/FiO₂ ratio less than 200 mmHg. Still, ARDS is feared (mortality 30-40%[1]) and relatively frequent (incidence between 13.5 per 100,000[2] to 75 per 100,000[3]). Acute lung injury (ALI) describes a similar, but less severe, clinical condition, with PaO₂/FiO₂ values between 200 and 300mmHg. Despite ongoing and intensive scientific research in this area, the mechanisms underlying ALI/ARDS are still not completely understood, and until recently, there were no studies demonstrating any beneficial effect of a single treatment modality in ARDS. The recent report that a specific approach to ventilatory support can significantly reduce mortality in ARDS underscores the need for better understanding of the pathophysiological events occurring in this syndrome. This review therefore summarizes the current pathophysiological concepts underlying the evolution of acute hypoxemic respiratory failure and focuses on: (1) possible reasons for the development of ALI/ARDS; (2) cellular and humoral mediator responses leading to a sustained and self-perpetuating inflammation of the lung; (3) consequences with regard to fluid balance, pulmonary perfusion, ventilation, and efficiency of gas exchange; and (4) mechanisms underlying the aggravating complications commonly seen in ARDS, especially ventilator-associated lung injury, ventilator-associated pneumonia, and lung fibrosis.

REFERENCES

• 1 The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.  New Engl J Med . 2000;  342 1301-1308
  CrossrefPubMedGoogle Scholar
• 2 Luhr O R, Antonsen K, Karlsson M, the ARF Study Group. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland.  Am J Respir Crit Care Med . 1999;  159 1849-1861
  PubMedGoogle Scholar
• 3 Ware L B, Matthay M A. The acute respiratory distress syndrome.  N Engl J Med . 2000;  342 1334-1349
  CrossrefPubMedGoogle Scholar
• 4 Hudson L D, Milberg J A, Anardi D, Maunder R J. Clinical risks for development of the acute respiratory distress syndrome.  Am J Respir Crit Care Med . 1995;  151 293-301
  CrossrefPubMedGoogle Scholar
• 5 Fein A M, Calalang-Colucci M G. Acute lung injury and acute respiratory distress syndrome in sepsis and septic shock.  Crit Care Clin . 2000;  16 289-317
  PubMedGoogle Scholar
• 6 Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation.  Eur Respir J . 2000;  16 534-554
  CrossrefPubMedGoogle Scholar
• 7 Abraham E. NF-kappaB activation.  Crit Care Med . 2000;  28 N100-104
  PubMedGoogle Scholar
• 8 Rahman I, MacNee W. Role of transcription factors in inflammatory lung diseases.  Thorax . 1998;  53 601-612
  CrossrefPubMedGoogle Scholar
• 9 Shanley T P, Warner R L, Ward P A. The role of cytokines and adhesion molecules in the development of inflammatory injury.  Mol Med Today . 1995;  1 40-45
  PubMedGoogle Scholar
• 10 Laufe M D, Simon R H, Flint A, Keller J B. Adult respiratory distress syndrome in neutropenic patients.  Am J Med . 1986;  80 1022-1026
  CrossrefPubMedGoogle Scholar
• 11 Pugin J, Ricou B, Steinberg K P, Suter P M, Martin T R. Proinflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1.  Am J Respir Crit Care Med . 1996;  153 1850-1856
  CrossrefPubMedGoogle Scholar
• 12 Millar A B, Foley N M, Singer M, Johnson N M, Meager A, Rook G A. Tumour necrosis factor in bronchopulmonary secretions of patients with adult respiratory distress syndrome.  Lancet . 1989;  2 712-714
  PubMedGoogle Scholar
• 13 Suter P M, Suter S, Giradin P, Roux-Lombard P, Grau G E, Dayer J M. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-a, interferon and elastase in patients with ARDS after trauma, shock or sepsis.  Am Rev Respir Dis . 1992;  145 1016-1022
  CrossrefPubMedGoogle Scholar
• 14 Hyers E R, Tricomi S M, Dettenmeier P A, Fowler A A. Tumor necrosis factor levels in serum and bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome.  Am Rev Respir Dis . 1991;  144 268-271
  PubMedGoogle Scholar
• 15 Rosseau S, Selhorst J, Wiechmann K. Monocyte migration through the alveolar epithelial barrier: adhesion molecule mechanisms and impact of chemokines.  J Immunol . 2000;  164 427-435
  PubMedGoogle Scholar
• 16 Seeger W, Walter H, Suttorp N, Muhly M, Bhakdi S. Thromboxane-mediated hypertension and vascular leakage evoked by low doses of Escherichia coli hemolysin in rabbit lungs.  J Clin Invest . 1989;  84 220-227
  PubMedGoogle Scholar
• 17 Klausner J M, Paterson I S, Mannick J A, Valeri R, Shepro D, Hechtman H B. Reperfusion pulmonary edema.  JAMA . 1989;  261 1030-1035
  CrossrefPubMedGoogle Scholar
• 18 Seeger W, Grimminger F. Leukotrienes and ARDS.  Intensive Care Med . 1991;  17 65-66
  CrossrefPubMedGoogle Scholar
• 19 Hill M E, Bird I N, Daniels R H, Elmore M A, Finnen M J. Endothelial cell-associated platelet-activating factor primes neutrophils for enhanced superoxide production and arachidonic acid release during adhesion to but not transmigration across IL-1 beta-treated endothelial monolayers.  J Immunol . 1994;  153 3673-3683
  PubMedGoogle Scholar
• 20 Grimminger F, Menger M, Becker G, Seeger W. Potentiation of leukotriene production following sequestration of neutrophils in isolated lungs: indirect evidence for intercellular leukotriene A₄ transfer.Blood .  1988;  72 1687-1692
  PubMedGoogle Scholar
• 21 Grimminger F, von Kurten I, Walmrath D, Seeger W. Type II alveolar epithelial eicosanoid metabolism: predominance of cyclooxygenase pathways and transcellular lipoxygenase metabolism in co-culture with neutrophils.  Am J Respir Cell Mol Biol . 1992;  6 9-16
  PubMedGoogle Scholar
• 22 Saldeen T. Clotting, microembolism, and inhibition of fibrinolysis in adult respiratory distress.  Surg Clin North Am . 1983;  63 285-304
  PubMedGoogle Scholar
• 23 Grau G E, Moerloose P, Bullao Lou J. Haemostatic properties of human pulmonary and cerebral microvascular endothelial cells.  Thromb Haemost . 1997;  77 585-590
  PubMedGoogle Scholar
• 24 Hara S, Asada Y, Hatakeyama K. Expression of tissue factor and tissue factor pathway inhibitor in rat lungs with lipopolysaccharide-induced disseminated intravascular coagulation.  Lab Invest . 1997;  77 581-589
  PubMedGoogle Scholar
• 25 Broze G J. Tissue factor pathway inhibitor and the revised theory of coagulation.  Annu Rev Medicine . 1995;  46 103-112
  PubMedGoogle Scholar
• 26 Schleef R R, Bevilacqua M P, Sawdey M, Gimbrone M A, Loskutoff D J. Cytokine activation of vascular endothelium: effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor.  J Biol Chem . 1988;  263 5797-5803
  PubMedGoogle Scholar
• 27 Bajaj M S, Kuppuswamy M N, Manepalli A N, Bajaj S P. Transcriptional expression of tissue factor pathway inhibitor, thrombomodulin and von Willebrand factor in normal human tissues.  Thromb Haemost . 1999;  82 1047-1052
  PubMedGoogle Scholar
• 28 MacGregor I R, Perrie A M, Donnelly S C, Haslett C. Modulation of human endothelial thrombomodulin by neutrophils and their release products.  Am J Respir Crit Care Med . 1997;  155 47-52
  PubMedGoogle Scholar
• 29 Bhakdi S, Walev I, Jonas D. Pathogenesis of sepsis syndrome: possible relevance of pore-forming bacterial toxins. In: Rietschel ET, Wagner H, eds. Current Topics in Microbiology and Immunology Vol 216. Berlin, Heidelberg: Springer-Verlag 1986: 101-116
  Google Scholar
• 30 Ermert L, Duncker H-R, Brückner H. Ultrastructural changes of lung capillary endothelium in response to botulinum C2 toxin.  J Appl Physiol . 1997;  82 382-388
  PubMedGoogle Scholar
• 31 Wiener-Kronish J P, Albertine K H, Matthay M A. Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin.  J Clin Invest . 1991;  88 864-875
  CrossrefPubMedGoogle Scholar
• 32 Yano T, Mason R J, Pan T, Deterding R R, Nielsen L D, Shannon J M. KGF regulates pulmonary epithelial proliferation and surfactant protein gene expression in adult rat lung.  Am J Physiol Lung Cell Mol Physiol . 2000;  279 L1146-1158
  PubMedGoogle Scholar
• 33 Seeger W, Neuhof H, Hall J, Roka L. Pulmonary vasoconstrictor response to soluble fibrin in isolated lungs: possible role of thromboxane generation.  Circ Res . 1988;  62 651-659
  PubMedGoogle Scholar
• 34 Griese M. Pulmonary surfactant in health and human lung diseases: state of the art.  Eur Respir J . 1999;  13 1455-1476
  PubMedGoogle Scholar
• 35 Jobe A H, Ikegami M. Surfactant and acute lung injury.  Proc Assoc Am Physicians . 1998;  110 489-495
  PubMedGoogle Scholar
• 36 Weaver T E. Synthesis, processing and secretion of surfactant proteins B and C.  Biochim Biophys Acta . 1998;  1408 173-179
  PubMedGoogle Scholar
• 37 Goerke J. Pulmonary surfactant: functions and molecular composition.  Biochim Biophys Acta . 1998;  1408 79-89
  CrossrefPubMedGoogle Scholar
• 38 Possmayer F. Biophysical activities of pulmonary surfactant. In: Polin RA, Fox WW, eds. Fetal and neonatal physiology Philadelphia: WB Saunders 1991: 959-962
  Google Scholar
• 39 Krishnasamy S, Gross N J, Teng A L, Schultz R M, Dhand R. Lung ``surfactant convertase'' is a member of the carboxylesterase family.  Biochem Biophys Res Commun . 1997;  235 180-184
  CrossrefPubMedGoogle Scholar
• 40 Nieman G F, Bredenberg C E. High surface tension pulmonary edema induced by detergent aerosol.  J Appl Physiol . 1985;  58 129-136
  PubMedGoogle Scholar
• 41 Wright J R. Immunomodulatory functions of surfactant.  Physiol Rev . 1997;  77 931-962
  PubMedGoogle Scholar
• 42 Jobe A H. Pulmonary surfactant therapy.  N Engl J Med . 1993;  328 861-868
  CrossrefPubMedGoogle Scholar
• 43 Seeger W, Günther A, Walmrath H D, Grimminger F, Lasch H G. Alveolar surfactant and adult respiratory distress syndrome: pathogenetic role and therapeutic prospects.  Clin Investig . 1993;  71 177-190
  PubMedGoogle Scholar
• 44 Günther A, Siebert C, Schmidt R. Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema.  Am J Respir Crit Care Med . 1996;  153 176-184
  PubMedGoogle Scholar
• 45 Hallman M, Spragg R, Harrell J H, Moser K M, Gluck L. Evidence of lung surfactant abnormality in respiratory failure: study of bronchoalveolar lavage phospholipids, surface activity, phospholipase activity, and plasma myoinositol.  J Clin Invest . 1982;  70 673-683
  PubMedGoogle Scholar
• 46 Gregory T J, Longmore W J, Moxley M A. Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome.  J Clin Invest . 1991;  88 1976-1981
  PubMedGoogle Scholar
• 47 Seeger W, Elssner A, Günther A, Kramer H J, Kalinowski H O. Lung surfactant phospholipids associate with polymerizing fibrin: loss of surface activity.  Am J Respir Cell Mol Biol . 1993;  9 213-220
  PubMedGoogle Scholar
• 48 Seeger W, Grube C, Günther A, Schmidt R. Surfactant inhibition by plasma proteins: differential sensitivity of various surfactant preparations.  Eur Respir J . 1993;  6 971-977
  PubMedGoogle Scholar
• 49 Seeger W, Günther A, Thede C. Differential sensitivity to fibrinogen inhibition of SP-C- versus SP-B-based surfactants.  Am J Physiol . 1992;  262 L286-L291
  PubMedGoogle Scholar
• 50 Günther A, Mosavi P, Heinemann S. 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
  PubMedGoogle Scholar
• 51 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
  PubMedGoogle Scholar
• 52 Pison U, Tam E K, Caughey G H, Hawgood S. Proteolytic inactivation of dog lung surfactant-associated proteins by neutrophil elastase.  Biochim Biophys Acta . 1989;  992 251-257
  PubMedGoogle Scholar
• 53 Baker C S, Evans T W, Randle B J, Haslam P L. Damage to surfactant-specific protein in acute respiratory distress syndrome.  Lancet . 1999;  353 1232-1237
  CrossrefPubMedGoogle Scholar
• 54 Gregory T J, Steinberg K P, Spragg R. Bovine surfactant therapy for patients with acute respiratory distress syndrome.  Am J Respir Crit Care Med . 1997;  155 1309-1315
  PubMedGoogle Scholar
• 55 Walmrath D, Günther A, Ghofrani H A. Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis.  Am J Respir Crit Care Med . 1996;  154 57-62
  PubMedGoogle Scholar
• 56 Walmrath D, Schneider T, Schermuly R, Olschewski H, Grimminger F, Seeger W. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome.  Am J Respir Crit Care Med . 1996;  153 991-996
  CrossrefPubMedGoogle Scholar
• 57 Roca J, Wagner P D. Contribution of multiple inert gas elimination technique to pulmonary medicine. 1. Principles and information content of the multiple inert gas elimination technique.Thorax .  1994;  49 815-824
  PubMedGoogle Scholar
• 58 Meduri G U, Reddy R C, Stanley T, El-Zeky F. Pneumonia in acute respiratory distress syndrome: a prospective evaluation of bilateral bronchoscopic sampling.  Am J Respir Crit Care Med . 1998;  158 870-875
  PubMedGoogle Scholar
• 59 Delclaux C, Roupie E, Blot F, Brochard L, Lemaire F, Brun-Buisson C. Lower respiratory tract colonization and infection during severe acute respiratory distress syndrome: incidence and diagnosis.  Am J Respir Crit Care Med . 1997;  156 1092-1098
  PubMedGoogle Scholar
• 60 Markowicz P, Wolff M, Djedaini K. Multicenter prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome: incidence, prognosis, and risk factors. ARDS Study Group.  Am J Respir Crit Care Med . 2000;  161 1942-1948
  PubMedGoogle Scholar
• 61 Chastre J, Trouillet J L, Vuagnat A. Nosocomial pneumonia in patients with acute respiratory distress syndrome.  Am J Respir Crit Care Med . 1998;  157 1165-1172
  PubMedGoogle Scholar
• 62 Maus U, Herold S, Muth H. Monocytes recruited into the alveolar air space of mice show a monocytic phenotype but upregulate CD14.  Am J Physiol Lung Cell Mol Physiol . 2001;  280 L58-L68
  PubMedGoogle Scholar
• 63 Crouch E, Hartshorn K, Ofek I. Collectins and pulmonary innate immunity.  Immunol Rev . 2000;  173 52-65
  CrossrefPubMedGoogle Scholar
• 64 Greene K E, Wright J R, Steinberg K P. Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS.  Am J Respir Crit Care Med . 1999;  160 1843-1850
  CrossrefPubMedGoogle Scholar
• 65 LeVine A M, Whitsett J A, Gwozdz J A. Distinct effects of surfactant protein A or D deficiency during bacterial infection on the lung.  J Immunol . 2000;  165 3934-3940
  PubMedGoogle Scholar
• 66 Seidenfeld J J, Pohl D F, Bell R C, Harris G D, Johanson Jr G W. Incidence, site, and outcome of infections in patients with the adult respiratory distress syndrome.  Am Rev Respir Dis . 1986;  134 12-16
  PubMedGoogle Scholar
• 67 International consensus conferences in intensive care medicine: ventilator-associated lung injury in ARDS. This official conference report was cosponsored by the American Thoracic Society, The European Society of Intensive Care Medicine, and The Societe de Reanimation de Langue Francaise, and was approved by the ATS Board of Directors, July 1999.  Am J Respir Crit Care Med . 1999;  160 2118-2124
  PubMedGoogle Scholar
• 68 Tremblay L, Valenza F, Ribeiro S P, Li J, Slutsky A S. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model.  J Clin Invest . 1997;  99 944-952
  CrossrefPubMedGoogle Scholar
• 69 Slutsky A S, Tremblay L N. Multiple system organ failure: is mechanical ventilation a contributing factor?.  Am J Respir Crit Care Med . 1998;  157 1721-1725
  PubMedGoogle Scholar
• 70 Dreyfuss D, Basset G, Soler P, Saumon G. Intermittent positive-pressure hyperventilation with high inflation pressures produces pulmonary microvascular injury in rats.  Am Rev Respir Dis . 1985;  132 880-884
  PubMedGoogle Scholar
• 71 Parker J C, Townsley M I, Rippe B, Taylor A E, Thigpen J. Increased microvascular permeability in dog lungs due to high peak airway pressures.  J Appl Physiol . 1984;  57 1809-1816
  PubMedGoogle Scholar
• 72 Tsuno K, Prato P, Kolobow T. Acute lung injury from mechanical ventilation at moderately high airway pressures.  J Appl Physiol . 1990;  69 956-961
  PubMedGoogle Scholar
• 73 Ito Y, Veldhuizen R A, Yao L J, McCaig L A, Bartlett A J, Lewis J F. Ventilation strategies affect surfactant aggregate conversion in acute lung injury.  Am J Respir Crit Care Med . 1997;  155 493-499
  PubMedGoogle Scholar
• 74 McHugh L G, Milberg J A, Whitcomb M E, Schoene R B, Maunder R J, Hudson L D. Recovery of function in survivors of the acute respiratory distress syndrome.  Am J Respir Crit Care Med . 1994;  150 90-94
  CrossrefPubMedGoogle Scholar
• 75 Meduri G U, Tolley E A, Chinn A, Stentz F, Postlethwaite A. Procollagen types I and III aminoterminal propeptide levels during acute respiratory distress syndrome and in response to methylprednisolone treatment.  Am J Respir Crit Care Med . 1998;  158 1432-1441
  PubMedGoogle Scholar
• 76 Armstrong L, Thickett D R, Mansell J P. Changes in collagen turnover in early acute respiratory distress syndrome.  Am J Respir Crit Care Med . 1999;  160 1910-1915
  PubMedGoogle Scholar
• 77 Marshall R P, Bellingan G, Webb S. Fibroproliferation occurs early in the acute respiratory distress syndrome and impacts on outcome.  Am J Respir Crit Care Med . 2000;  162 1783-1788
  PubMedGoogle Scholar
• 78 Madtes D K, Rubenfeld G, Klima L D. Elevated transforming growth factor-alpha levels in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome.  Am J Respir Crit Care Med . 1998;  158 424-430
  PubMedGoogle Scholar
• 79 Thrall R S, McCormick J R, Jack R M, McReynolds R A, Ward P A. Bleomycin-induced pulmonary fibrosis in the rat. Inhibition by indomethacin.  Am J Pathol . 1979;  95 117-130
  PubMedGoogle Scholar
• 80 Jones H A, Schofield J B, Krausz T, Boobis A R, Haslett C. Pulmonary fibrosis correlates with duration of tissue neutrophil activation.  Am J Respir Crit Care Med . 1998;  158 620-628
  PubMedGoogle Scholar
• 81 Piguet P F, Haufman S, Barazzone C, Muller M, Ryffel B, Eugster H P. Resistance of TNF/LT alpha double deficient mice to bleomycin-induced fibrosis.  Int J Exp Pathol . 1997;  78 43-48
  CrossrefPubMedGoogle Scholar
• 82 Zhang K, Gharaee-Kermani M, McGarry B, Remick D, Phan S H. TNF-alpha mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis.  J Immunol . 1997;  158 954-959
  PubMedGoogle Scholar
• 83 Lasky J A, Ortiz L A, Tonthat B. Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis.  Am J Physiol . 1998;  275 L365-L371
  PubMedGoogle Scholar
• 84 Coker R K, Laurent G J, Shahzeidi S. Transforming growth factors-beta 1, -beta 2, and -beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin induced lung fibrosis.  Am J Pathol . 1997;  150 981-991
  PubMedGoogle Scholar
• 85 Temelkovski J, Kumar R K, Maronese S E. Enhanced production of an EGF-like growth factor by parenchymal macrophages following bleomycin-induced pulmonary injury.  Exp Lung Res . 1997;  23 377-391
  PubMedGoogle Scholar
• 86 Blobe G C, Schiemann W P, Lodish H F. Role of transforming growth factor beta in human disease.  N Engl J Med . 2000;  342 1350-1358
  CrossrefPubMedGoogle Scholar
• 87 Günther A, Schmidt R, Nix F. Surfactant abnormalities in idiopathic pulmonary fibrosis, hypersensitivity pneumonitis and sarcoidosis.  Eur Respir J . 1999;  14 565-573
  CrossrefPubMedGoogle Scholar
• 88 Günther A, Markart P, Kalinowski M, Ruppert C, Grimminger F, Seeger W. Cleavage of surfactant-incorporating fibrin by different fibrinolytic agents: kinetics of lysis and rescue of surface activity.  Am J Respir Cell Mol Biol . 1999;  21 738-745
  PubMedGoogle Scholar
• 89 Günther A, Mosavi P, Ruppert C. Enhanced tissue factor pathway activity and fibrin turnover in the alveolar compartment of patients with interstitial lung disease.  Thromb Haemost . 2000;  83 853-860
  PubMedGoogle Scholar
• 90 Burkhardt A. Alveolitis and collapse in the pathogenesis of pulmonary fibrosis.  Am Rev Respir Dis . 1989;  140 513-524
  PubMedGoogle Scholar
• 91 Ohba T, McDonald J K, Silver R M, Strange C, Carwile LeRoy E, Ludwicka A. Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor α-receptor.  Am J Respir Cell Mol Biol . 1994;  10 405
  PubMedGoogle Scholar
• 92 Hernandez-Rodriguez N A, Harrison N K, Chambers C. Role of thrombin in pulmonary fibrosis.  Lancet . 1995;  346 1071-1073
  CrossrefPubMedGoogle Scholar
• 93 Gray A J, Bishop J E, Reeves J T, Mecham R P, Laurent G J. Partially degraded fibrin(ogen) stimulates fibroblast proliferation in vitro.  Am J Respir Mol Cell Biol . 1995;  12 684-690
  PubMedGoogle Scholar
• 94 Swaisgood C M, French E L, Noga C, Simon R H, Ploplis V A. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system.  Am J Pathol . 2000;  157 177-187
  CrossrefPubMedGoogle Scholar
• 95 Eitzman D T, McCoy R D, Zheng X. 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
  CrossrefPubMedGoogle Scholar