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Semin Respir Crit Care Med 2013; 34(04): 537-548
DOI: 10.1055/s-0033-1351124
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Biomarkers of ALI/ARDS: Pathogenesis, Discovery, and Relevance to Clinical Trials

David R. Janz
1   Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
,
Lorraine B. Ware
1   Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
2   Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
› Author Affiliations
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Publication History

Publication Date:
11 August 2013 (online)

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Abstract

Despite the high incidence and poor prognosis of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), it remains challenging to identify patients who are at highest risk of developing these syndromes, differentiate these syndromes from other causes of acute respiratory failure, and accurately prognosticate once the diagnosis is made. The identification and validation of biological markers of ALI has the potential to ameliorate these challenges by facilitating studies of therapies aimed at prevention, identifying patients more accurately that have ALI so they can benefit from evidence-based therapies and enrollment in clinical trials, and determining which patients are unlikely to have a positive outcome to guide therapeutic choices and trials of experimental rescue therapies. This article reviews the current state of biomarker research in ALI/ARDS. New methodologies for identification of novel biomarkers of ALI, including metabolomics, proteomics, gene expression, and genetic studies are also discussed.

Keywords

acute lung injury - biomarker - metabolomics - proteomics - genomics - genetics - acute respiratory distress syndrome
 

  • References

  • 1 Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342 (18) 1334-1349
    CrossrefPubMedSearch in Google Scholar
  • 2 Rubenfeld GD, Caldwell E, Peabody E , et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353 (16) 1685-1693
    CrossrefPubMedSearch in Google Scholar
  • 3 Biomarkers Definitions Working Group.. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69 (3) 89-95
    CrossrefPubMedSearch in Google Scholar
  • 4 WHO International Programme on Chemical Safety. Biomarkers in risk assessment: validity and validation. 2001. http://www.inchem.org/documents/ehc/ehc/ehc155.htm
    PubMed
  • 5 Eisner MD, Parsons P, Matthay MA, Ware L, Greene K. Acute Respiratory Distress Syndrome Network. Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 2003; 58 (11) 983-988
    CrossrefPubMedSearch in Google Scholar
  • 6 McClintock DE, Ware LB, Eisner MD, Wickersham N, Thompson BT, Matthay MA. National Heart, Lung, and Blood Institute ARDS Network. Higher urine nitric oxide is associated with improved outcomes in patients with acute lung injury. Am J Respir Crit Care Med 2007; 175 (3) 256-262
    CrossrefPubMedSearch in Google Scholar
  • 7 Suratt BT, Eisner MD, Calfee CS , et al; NHLBI Acute Respiratory Distress Syndrome Network. Plasma granulocyte colony-stimulating factor levels correlate with clinical outcomes in patients with acute lung injury. Crit Care Med 2009; 37 (4) 1322-1328
    CrossrefPubMedSearch in Google Scholar
  • 8 Ware LB, Eisner MD, Thompson BT, Parsons PE, Matthay MA. Significance of von Willebrand factor in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care Med 2004; 170 (7) 766-772
    CrossrefPubMedSearch in Google Scholar
  • 9 Parsons PE, Eisner MD, Thompson BT , et al; NHLBI Acute Respiratory Distress Syndrome Clinical Trials Network. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005; 33 (1) 1-6 , discussion 230–232
    PubMedSearch in Google Scholar
  • 10 Ware LB, Fang X, Matthay MA. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003; 285 (3) L514-L521
    CrossrefPubMedSearch in Google Scholar
  • 11 Parsons PE, Matthay MA, Ware LB, Eisner MD. National Heart, Lung, Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network. Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol 2005; 288 (3) L426-L431
    CrossrefPubMedSearch in Google Scholar
  • 12 Calfee CS, Eisner MD, Parsons PE , et al; NHLBI Acute Respiratory Distress Syndrome Clinical Trials Network. Soluble intercellular adhesion molecule-1 and clinical outcomes in patients with acute lung injury. Intensive Care Med 2009; 35 (2) 248-257
    CrossrefPubMedSearch in Google Scholar
  • 13 Calfee CS, Ware LB, Eisner MD , et al; NHLBI ARDS Network. Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury. Thorax 2008; 63 (12) 1083-1089
    CrossrefPubMedSearch in Google Scholar
  • 14 Ware LB, Fremont RD, Bastarache JA, Calfee CS, Matthay MA. Determining the aetiology of pulmonary oedema by the oedema fluid-to-plasma protein ratio. Eur Respir J 2010; 35 (2) 331-337
    CrossrefPubMedSearch in Google Scholar
  • 15 Matthay MA, Zemans RL. The acute respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol 2011; 6: 147-163
    CrossrefPubMedSearch in Google Scholar
  • 16 Zimmerman GA, Albertine KH, Carveth HJ , et al. Endothelial activation in ARDS. Chest 1999; 116 (1, Suppl): 18S-24S
    CrossrefPubMedSearch in Google Scholar
  • 17 Staub NC. Pulmonary edema due to increased microvascular permeability. Annu Rev Med 1981; 32: 291-312
    CrossrefPubMedSearch in Google Scholar
  • 18 Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol 2006; 27 (12) 552-558
    CrossrefPubMedSearch in Google Scholar
  • 19 Parikh SM, Mammoto T, Schultz A , et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med 2006; 3 (3) e46
    CrossrefPubMedSearch in Google Scholar
  • 20 Fiedler U, Reiss Y, Scharpfenecker M , et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 2006; 12 (2) 235-239
    CrossrefPubMedSearch in Google Scholar
  • 21 Bhandari V, Choo-Wing R, Lee CG , et al. Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat Med 2006; 12 (11) 1286-1293
    CrossrefPubMedSearch in Google Scholar
  • 22 van der Heijden M, van Nieuw Amerongen GP, Koolwijk P, van Hinsbergh VW, Groeneveld AB. Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients. Thorax 2008; 63 (10) 903-909
    CrossrefPubMedSearch in Google Scholar
  • 23 Gallagher DC, Parikh SM, Balonov K , et al. Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome. Shock 2008; 29 (6) 656-661
    PubMedSearch in Google Scholar
  • 24 Calfee CS, Gallagher D, Abbott J, Thompson BT, Matthay MA. NHLBI ARDS Network. Plasma angiopoietin-2 in clinical acute lung injury: prognostic and pathogenetic significance. Crit Care Med 2012; 40 (6) 1731-1737
    CrossrefPubMedSearch in Google Scholar
  • 25 Langer HF, Chavakis T. Leukocyte-endothelial interactions in inflammation. J Cell Mol Med 2009; 13 (7) 1211-1220
    CrossrefPubMedSearch in Google Scholar
  • 26 Newman W, Beall LD, Carson CW , et al. Soluble E-selectin is found in supernatants of activated endothelial cells and is elevated in the serum of patients with septic shock. J Immunol 1993; 150 (2) 644-654
    PubMedSearch in Google Scholar
  • 27 Gearing AJ, Newman W. Circulating adhesion molecules in disease. Immunol Today 1993; 14 (10) 506-512
    CrossrefPubMedSearch in Google Scholar
  • 28 Okajima K. Regulation of inflammatory responses by natural anticoagulants. Immunol Rev 2001; 184: 258-274
    CrossrefPubMedSearch in Google Scholar
  • 29 Okajima K, Harada N, Sakurai G , et al. Rapid assay for plasma soluble E-selectin predicts the development of acute respiratory distress syndrome in patients with systemic inflammatory response syndrome. Transl Res 2006; 148 (6) 295-300
    CrossrefPubMedSearch in Google Scholar
  • 30 Donnelly SC, Haslett C, Dransfield I , et al. Role of selectins in development of adult respiratory distress syndrome. Lancet 1994; 344 (8917) 215-219
    CrossrefPubMedSearch in Google Scholar
  • 31 Franchini M, Lippi G. Von Willebrand factor and thrombosis. Ann Hematol 2006; 85 (7) 415-423
    CrossrefPubMedSearch in Google Scholar
  • 32 Rubin DB, Wiener-Kronish JP, Murray JF , et al. Elevated von Willebrand factor antigen is an early plasma predictor of acute lung injury in nonpulmonary sepsis syndrome. J Clin Invest 1990; 86 (2) 474-480
    CrossrefPubMedSearch in Google Scholar
  • 33 Ware LB, Conner ER, Matthay MA. von Willebrand factor antigen is an independent marker of poor outcome in patients with early acute lung injury. Crit Care Med 2001; 29 (12) 2325-2331
    CrossrefPubMedSearch in Google Scholar
  • 34 Bajaj MS, Tricomi SM. Plasma levels of the three endothelial-specific proteins von Willebrand factor, tissue factor pathway inhibitor, and thrombomodulin do not predict the development of acute respiratory distress syndrome. Intensive Care Med 1999; 25 (11) 1259-1266
    CrossrefPubMedSearch in Google Scholar
  • 35 Moss M, Ackerson L, Gillespie MK, Moore FA, Moore EE, Parsons PE. von Willebrand factor antigen levels are not predictive for the adult respiratory distress syndrome. Am J Respir Crit Care Med 1995; 151 (1) 15-20
    CrossrefPubMedSearch in Google Scholar
  • 36 Muller WA. Mechanisms of transendothelial migration of leukocytes. Circ Res 2009; 105 (3) 223-230
    CrossrefPubMedSearch in Google Scholar
  • 37 Conner ER, Ware LB, Modin G, Matthay MA. Elevated pulmonary edema fluid concentrations of soluble intercellular adhesion molecule-1 in patients with acute lung injury: biological and clinical significance. Chest 1999; 116 (1, Suppl): 83S-84S
    CrossrefPubMedSearch in Google Scholar
  • 38 McClintock D, Zhuo H, Wickersham N, Matthay MA, Ware LB. Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury. Crit Care 2008; 12 (2) R41
    CrossrefPubMedSearch in Google Scholar
  • 39 Flori HR, Ware LB, Glidden D, Matthay MA. Early elevation of plasma soluble intercellular adhesion molecule-1 in pediatric acute lung injury identifies patients at increased risk of death and prolonged mechanical ventilation. Pediatr Crit Care Med 2003; 4 (3) 315-321
    CrossrefPubMedSearch in Google Scholar
  • 40 Medford ARL, Millar AB. Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): paradox or paradigm?. Thorax 2006; 61 (7) 621-626
    CrossrefPubMedSearch in Google Scholar
  • 41 Ware LB, Kaner RJ, Crystal RG , et al. VEGF levels in the alveolar compartment do not distinguish between ARDS and hydrostatic pulmonary oedema. Eur Respir J 2005; 26 (1) 101-105
    CrossrefPubMedSearch in Google Scholar
  • 42 Wiener-Kronish JP, Albertine KH, Matthay MA. Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin. J Clin Invest 1991; 88 (3) 864-875
    CrossrefPubMedSearch in Google Scholar
  • 43 Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001; 163 (6) 1376-1383
    CrossrefPubMedSearch in Google Scholar
  • 44 Lewis JF, Jobe AH. Surfactant and the adult respiratory distress syndrome. Am Rev Respir Dis 1993; 147 (1) 218-233
    CrossrefPubMedSearch in Google Scholar
  • 45 Kurahashi K, Kajikawa O, Sawa T , et al. Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia. J Clin Invest 1999; 104 (6) 743-750
    CrossrefPubMedSearch in Google Scholar
  • 46 Bitterman PB. Pathogenesis of fibrosis in acute lung injury. Am J Med 1992; 92 (6A) 39S-43S
    PubMedSearch in Google Scholar
  • 47 Pastva AM, Wright JR, Williams KL. Immunomodulatory roles of surfactant proteins A and D: implications in lung disease. Proc Am Thorac Soc 2007; 4 (3) 252-257
    CrossrefPubMedSearch in Google Scholar
  • 48 Chroneos ZC, Sever-Chroneos Z, Shepherd VL. Pulmonary surfactant: an immunological perspective. Cell Physiol Biochem 2010; 25 (1) 13-26
    CrossrefPubMedSearch in Google Scholar
  • 49 Greene KE, Wright JR, Steinberg KP , et al. Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS. Am J Respir Crit Care Med 1999; 160 (6) 1843-1850
    CrossrefPubMedSearch in Google Scholar
  • 50 Greene KE, Ye S, Mason RJ, Parsons PE. Serum surfactant protein-A levels predict development of ARDS in at-risk patients. Chest 1999; 116 (1, Suppl): 90S-91S
    CrossrefPubMedSearch in Google Scholar
  • 51 Bersten AD, Hunt T, Nicholas TE, Doyle IR. Elevated plasma surfactant protein-B predicts development of acute respiratory distress syndrome in patients with acute respiratory failure. Am J Respir Crit Care Med 2001; 164 (4) 648-652
    CrossrefPubMedSearch in Google Scholar
  • 52 Shirasawa M, Fujiwara N, Hirabayashi S , et al. Receptor for advanced glycation end-products is a marker of type I lung alveolar cells. Genes Cells 2004; 9 (2) 165-174
    CrossrefPubMedSearch in Google Scholar
  • 53 Uchida T, Shirasawa M, Ware LB , et al. Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med 2006; 173 (9) 1008-1015
    CrossrefPubMedSearch in Google Scholar
  • 54 Calfee CS, Budev MM, Matthay MA , et al. Plasma receptor for advanced glycation end-products predicts duration of ICU stay and mechanical ventilation in patients after lung transplantation. J Heart Lung Transplant 2007; 26 (7) 675-680
    CrossrefPubMedSearch in Google Scholar
  • 55 Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy 2000; 30 (4) 469-475
    CrossrefPubMedSearch in Google Scholar
  • 56 Determann RM, Millo JL, Waddy S, Lutter R, Garrard CS, Schultz MJ. Plasma CC16 levels are associated with development of ALI/ARDS in patients with ventilator-associated pneumonia: a retrospective observational study. BMC Pulm Med 2009; 9: 49
    CrossrefPubMedSearch in Google Scholar
  • 57 Kropski JA, Fremont RD, Calfee CS, Ware LB. Clara cell protein (CC16), a marker of lung epithelial injury, is decreased in plasma and pulmonary edema fluid from patients with acute lung injury. Chest 2009; 135 (6) 1440-1447
    CrossrefPubMedSearch in Google Scholar
  • 58 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. N Engl J Med 2000; 342 (18) 1301-1308
    CrossrefPubMedSearch in Google Scholar
  • 59 Meduri GU, Headley S, Kohler G , et al. Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 1995; 107 (4) 1062-1073
    CrossrefPubMedSearch in Google Scholar
  • 60 Park WY, Goodman RB, Steinberg KP , et al. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2001; 164 (10 Pt 1) 1896-1903
    CrossrefPubMedSearch in Google Scholar
  • 61 Takala A, Jousela I, Takkunen O , et al. A prospective study of inflammation markers in patients at risk of indirect acute lung injury. Shock 2002; 17 (4) 252-257
    CrossrefPubMedSearch in Google Scholar
  • 62 Parsons PE, Moss M, Vannice JL, Moore EE, Moore FA, Repine JE. Circulating IL-1ra and IL-10 levels are increased but do not predict the development of acute respiratory distress syndrome in at-risk patients. Am J Respir Crit Care Med 1997; 155 (4) 1469-1473
    CrossrefPubMedSearch in Google Scholar
  • 63 Bouros D, Alexandrakis MG, Antoniou KM , et al. The clinical significance of serum and bronchoalveolar lavage inflammatory cytokines in patients at risk for Acute Respiratory Distress Syndrome. BMC Pulm Med 2004; 4: 6
    CrossrefPubMedSearch in Google Scholar
  • 64 Pittet JF, Mackersie RC, Martin TR, Matthay MA. Biological markers of acute lung injury: prognostic and pathogenetic significance. Am J Respir Crit Care Med 1997; 155 (4) 1187-1205
    CrossrefPubMedSearch in Google Scholar
  • 65 Suter PM, Suter S, Girardin E, Roux-Lombard P, Grau GE, Dayer JM. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis 1992; 145 (5) 1016-1022
    CrossrefPubMedSearch in Google Scholar
  • 66 Donnelly SC, Strieter RM, Kunkel SL , et al. Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups. Lancet 1993; 341 (8846) 643-647
    CrossrefPubMedSearch in Google Scholar
  • 67 Goodman RB, Strieter RM, Martin DP , et al. Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1996; 154 (3 Pt 1) 602-611
    CrossrefPubMedSearch in Google Scholar
  • 68 Cohen MJ, Brohi K, Calfee CS , et al. Early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion. Crit Care 2009; 13 (6) R174
    CrossrefPubMedSearch in Google Scholar
  • 69 Bastarache JA, Ware LB, Bernard GR. The role of the coagulation cascade in the continuum of sepsis and acute lung injury and acute respiratory distress syndrome. Semin Respir Crit Care Med 2006; 27 (4) 365-376
    Thieme ConnectPubMedSearch in Google Scholar
  • 70 Prabhakaran P, Ware LB, White KE, Cross MT, Matthay MA, Olman MA. 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 (1) L20-L28
    CrossrefPubMedSearch in Google Scholar
  • 71 Ware LB, Matthay MA, Parsons PE, Thompson BT, Januzzi JL, Eisner MD. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med 2007; 35 (8) 1821-1828
    CrossrefPubMedSearch in Google Scholar
  • 72 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 Physiol 1991; 261 (4 Pt 1) L240-L248
    PubMedSearch in Google Scholar
  • 73 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 (1) 163-167
    CrossrefPubMedSearch in Google Scholar
  • 74 Günther 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 (2 Pt 1) 454-462
    CrossrefPubMedSearch in Google Scholar
  • 75 Bastarache JA, Wang L, Geiser T , et al. The alveolar epithelium can initiate the extrinsic coagulation cascade through expression of tissue factor. Thorax 2007; 62 (7) 608-616
    CrossrefPubMedSearch in Google Scholar
  • 76 Fremont RD, Koyama T, Calfee CS , et al. Acute lung injury in patients with traumatic injuries: utility of a panel of biomarkers for diagnosis and pathogenesis. J Trauma 2010; 68 (5) 1121-1127
    CrossrefPubMedSearch in Google Scholar
  • 77 Calfee CS, Ware LB, Glidden DV , et al; National Heart, Blood, and Lung Institute Acute Respiratory Distress Syndrome Network. Use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury. Crit Care Med 2011; 39 (4) 711-717
    CrossrefPubMedSearch in Google Scholar
  • 78 Ware LB, Koyama T, Billheimer DD , et al; NHLBI ARDS Clinical Trials Network. Prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury. Chest 2010; 137 (2) 288-296
    CrossrefPubMedSearch in Google Scholar
  • 79 Lacy P. Metabolomics of sepsis-induced acute lung injury: a new approach for biomarkers. Am J Physiol Lung Cell Mol Physiol 2011; 300 (1) L1-L3
    CrossrefPubMedSearch in Google Scholar
  • 80 Stringer KA, Serkova NJ, Karnovsky A, Guire K, Paine III R, Standiford TJ. Metabolic consequences of sepsis-induced acute lung injury revealed by plasma 1H-nuclear magnetic resonance quantitative metabolomics and computational analysis. Am J Physiol Lung Cell Mol Physiol 2011; 300 (1) L4-L11
    CrossrefPubMedSearch in Google Scholar
  • 81 Schnapp LM, Donohoe S, Chen J , et al. Mining the acute respiratory distress syndrome proteome: identification of the insulin-like growth factor (IGF)/IGF-binding protein-3 pathway in acute lung injury. Am J Pathol 2006; 169 (1) 86-95
    CrossrefPubMedSearch in Google Scholar
  • 82 de Torre C, Ying SX, Munson PJ, Meduri GU, Suffredini AF. Proteomic analysis of inflammatory biomarkers in bronchoalveolar lavage. Proteomics 2006; 6 (13) 3949-3957
    CrossrefPubMedSearch in Google Scholar
  • 83 Ware LB, Matthay MA. Beyond fishing: the role of discovery proteomics in mechanistic lung research. Am J Physiol Lung Cell Mol Physiol 2009; 296 (1) L12-L13
    PubMedSearch in Google Scholar
  • 84 Christie JD, Wurfel MM, Feng R , et al; Trauma ALI SNP Consortium (TASC) investigators. Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma. PLoS ONE 2012; 7 (1) e28268
    CrossrefPubMedSearch in Google Scholar
  • 85 Howrylak JA, Dolinay T, Lucht L , et al. Discovery of the gene signature for acute lung injury in patients with sepsis. Physiol Genomics 2009; 37 (2) 133-139
    CrossrefPubMedSearch in Google Scholar
  • 86 Wang Z, Beach D, Su L, Zhai R, Christiani DC. A genome-wide expression analysis in blood identifies pre-elafin as a biomarker in ARDS. Am J Respir Cell Mol Biol 2008; 38 (6) 724-732
    CrossrefPubMedSearch in Google Scholar
  • 87 Wang Z, Chen F, Zhai R , et al. Plasma neutrophil elastase and elafin imbalance is associated with acute respiratory distress syndrome (ARDS) development. PLoS ONE 2009; 4 (2) e4380
    CrossrefPubMedSearch in Google Scholar
  • 88 Brun-Buisson C, Minelli C, Bertolini G , et al; ALIVE Study Group. Epidemiology and outcome of acute lung injury in European intensive care units. Results from the ALIVE study. Intensive Care Med 2004; 30 (1) 51-61
    CrossrefPubMedSearch in Google Scholar
  • 89 Matthay MA, Brower RG, Carson S , et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Randomized, placebo-controlled clinical trial of an aerosolized β2-agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011; 184 (5) 561-568
    CrossrefPubMedSearch in Google Scholar
  • 90 Rice TW, Wheeler AP, Thompson BT, deBoisblanc BP, Steingrub J, Rock P. NIH NHLBI Acute Respiratory Distress Syndrome Network of Investigators. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA 2011; 306 (14) 1574-1581
    CrossrefPubMedSearch in Google Scholar
  • 91 Rice TW, Wheeler AP, Thompson BT , et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012; 307 (8) 795-803
    CrossrefPubMedSearch in Google Scholar
  • 92 Brower RG, Lanken PN, MacIntyre N , et al; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351 (4) 327-336
    CrossrefPubMedSearch in Google Scholar
  • 93 Steinberg KP, Hudson LD, Goodman RB , et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006; 354 (16) 1671-1684
    CrossrefPubMedSearch in Google Scholar
  • 94 Wiedemann HP, Wheeler AP, Bernard GR , et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006; 354 (24) 2564-2575
    CrossrefPubMedSearch in Google Scholar
  • 95 Ware LB. Prognostic determinants of acute respiratory distress syndrome in adults: impact on clinical trial design. Crit Care Med 2005; 33 (3, Suppl) S217-S222
    CrossrefPubMedSearch in Google Scholar