Elsevier

Critical Care Clinics

Volume 27, Issue 3, July 2011, Pages 661-683
Critical Care Clinics

Biomarkers in Acute Lung Injury—Marking Forward Progress

https://doi.org/10.1016/j.ccc.2011.04.001Get rights and content

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Biomarker research in ALI: definitions and goals

A widely cited definition for a biomarker came from the 1998 National Institutes of Health Biomarker Definitions Working Group: “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”.4 This definition makes no supposition about the material nature of the characteristic in question. Reflecting this, the World Health Organization suggests that a biomarker is “any

The biomarker and ALI interface

ALI and ARDS are complex, inflammatory syndromes of noncardiogenic pulmonary edema. Nonpulmonary sepsis and pneumonia are the most common causes followed by major trauma, shock, and aspiration of gastric contents.19 Injury to and permeabilization of endothelial and alveolar epithelial membranes, by a variety of injurious stimuli, leads to flooding of the alveolar compartment with protein-rich edema fluid, neutrophils, cellular debris, and inflammatory mediators. Multiple overlapping biologic

Biomarkers of acute lung injury—a rational classification

Biomarkers of ALI can be classified according to clinical, molecular biologic, or pathophysiologic dimensions. A clinical classification should take into consideration the underlying cause of lung injury, the phase of disease (early exudative or late fibroproliferative), and the site of sampling. Biomarkers of ALI may be measured in exhaled breath condensate, undiluted pulmonary edema fluid, saline-diluted bronchoalveolar lavage (BAL), plasma, serum, whole blood for gene expression analysis,

Inflammation and Cytokines

ALI is characterized by intra-alveolar inflammation mediated in part by proinflammatory cytokines. Differing cytokine profiles are characteristic of the early stages of ALI (termed early response cytokines) compared with the later fibroproliferative phase. Rising levels of inflammatory cytokines might be expected to precede the development of ALI in the at-risk patient population. Cytokines that have been identified in ALI include the interleukins (ILs), IL-2, IL-6, IL-8, IL-10, and IL-1β and

Protein biomarkers for diagnosis of ALI

Distinct from prediction of ALI in at-risk patients is the use of biomarkers to confirm the diagnosis of ALI similar to the use of cardiac troponins for myocardial infarction.70 Ideally a biomarker would function and perform under all clinical conditions (ie, be universal). For biomarker characterization, however, it is useful to specify the control group (patients with cardiogenic pulmonary edema, patients in an ICU with clear chest radiographs, normal controls, or patients at risk) against

Combining biomarkers for diagnosis of ALI

Given the failure of a single biomarker to discriminate ALI with high accuracy, the question arises whether a composite of biomarkers that represent the most commonly identified and clinically validated biologic ontologies (inflammation, endothelial activation, lung epithelial injury, and coagulation/altered fibrinolysis) might have better performance than any individual biomarker for diagnosis for ALI. As discussed previously, Fremont and colleagues76 posed this question with regards to the

Protein biomarkers for predicting outcome in ALI

Much of the strongest evidence in the field of ALI biomarkers comes from outcome prediction. Several biomarkers belonging to the biologic ontologies (discussed previously) have been validated in large multicenter clinical trials principally from ARDSNet. The outcomes most commonly predicted are hospital, 30-day, 60-day, or 180-day mortality; ventilator-free and organ-failure–free days; and assessment of response to low-tidal volume ventilation. The majority of this work has been performed in

Stem Cells

Adult-derived stem cells have been studied as biomarkers in ALI. Circulating endothelial progenitor cells have attracted attention recently as prognostic as well as potential therapeutic targets in ALI.99 A handful of studies have shown a small but consistent effect linking higher circulating levels of endothelial progenitor cells with survival from ALI,100, 101 suggesting that mobilization of endothelial progenitor cells in periods of acute stress may be beneficial.

Exhaled Breath Condensate

The exhaled breath

Summary

Is progress being made? This review has identified 4 areas where significant progress has been made over the last 10 years. The first area is the large-scale validation of several candidate biomarkers from a range of biologic pathways (IL-8, IL-6, vWF, protein C, PAI-1, and SP-D) for prognostication and mortality prediction. The second area is several novel predictors still requiring validation, mediating endothelial permeability (Ang-2), epithelial cell injury (CC-16), and inflammation (DcR

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References (120)

  • J.A. Kropski et al.

    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)
  • J. Tzu et al.

    Bridging structure with function: structural, regulatory, and developmental role of laminins

    Int J Biochem Cell Biol

    (2008)
  • E.R. Conner et al.

    Elevated pulmonary edema fluid concentrations of soluble intercellular adhesion molecule-1 in patients with acute lung injury: biological and clinical significance

    Chest

    (1999)
  • E.K. Bajwa et al.

    Plasma C-reactive protein levels are associated with improved outcome in ARDS

    Chest

    (2009)
  • M.A. Matthay et al.

    Therapeutic potential of mesenchymal stem cells for severe acute lung injury

    Chest

    (2010)

  • 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)
  • M.D. Eisner et al.

    Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury

    Thorax

    (2003)

  • Biomarkers and surrogate endpoints: preferred definitions and conceptual framework

    Clin Pharmacol Ther

    (2001)
  • WHO International Programme on Chemical Safety

    Biomarkers in risk assessment: validity and validation

  • WHO International Programme on Chemical Safety

    Biomarkers in risk assessment: validity and validation

  • K. Strimbu et al.

    What are biomarkers?

    Curr Opin HIV AIDS

    (2010)
  • R.G. Spragg et al.

    Beyond mortality: future clinical research in acute lung injury

    Am J Respir Crit Care Med

    (2010)
  • L.B. Ware et al.

    Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome

    Crit Care Med

    (2007)
  • J.C. Marshall et al.

    Biomarkers of sepsis

    Crit Care Med

    (2009)
  • D.F. Willson et al.

    Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial

    JAMA

    (2005)
  • A. Tzouvelekis et al.

    Serum biomarkers in acute respiratory distress syndrome an ailing prognosticator

    Respir Res

    (2005)
  • M.A. Olman et al.

    Pulmonary edema fluid from patients with early lung injury stimulates fibroblast proliferation through IL-1 beta-induced IL-6 expression

    J Immunol

    (2004)
  • K. Soreide

    Receiver-operating characteristic curve analysis in diagnostic, prognostic and predictive biomarker research

    J Clin Pathol

    (2009)
  • W. Zhu et al.

    Sensitivity, Specificity, Accuracy, Associated Confidence Interval and ROC Analysis with Practical SAS Implementations

  • Y. Shehabi et al.

    Pro/Con debate: is procalcitonin useful for guiding antibiotic decision making in critically ill patients?

    Crit Care

    (2008)
  • Kaufman RA, Oakley-Brown H, Watkins R, et al. Strategic planning for success: aligning people, performance, and...
  • L.B. Ware et al.

    The acute respiratory distress syndrome

    N Engl J Med

    (2000)
  • J.E. Levitt et al.

    The pathogenetic and prognostic value of biologic markers in acute lung injury

    J Intensive Care Med

    (2009)
  • Y. Imai et al.

    Angiotensin-converting enzyme 2 protects from severe acute lung failure

    Nature

    (2005)
  • P. Tejera et al.

    Genetic polymorphisms of peptidase inhibitor 3 (elafin) are associated with acute respiratory distress syndrome

    Am J Respir Cell Mol Biol

    (2009)
  • P.E. Parsons et al.

    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)
  • L. Gao et al.

    Recent advances in genetic predisposition to clinical acute lung injury

    Am J Physiol Lung Cell Mol Physiol

    (2009)
  • M.A. Matthay et al.

    Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management

    Am J Respir Cell Mol Biol

    (2005)
  • J.A. Bastarache et al.

    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)
  • L.B. Ware et al.

    Determining the aetiology of pulmonary oedema by the oedema fluid-to-plasma protein ratio

    Eur Respir J

    (2010)
  • H. Kitano

    Systems biology: a brief overview

    Science

    (2002)
  • W.Y. Park et al.

    Cytokine balance in the lungs of patients with acute respiratory distress syndrome

    Am J Respir Crit Care Med

    (2001)
  • P.E. Parsons et al.

    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)
  • D. Bouros 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)
  • J.F. Pittet et al.

    Biological markers of acute lung injury: prognostic and pathogenetic significance

    Am J Respir Crit Care Med

    (1997)
  • P.M. Suter et al.

    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)
  • A. Takala et al.

    A prospective study of inflammation markers in patients at risk of indirect acute lung injury

    Shock

    (2002)
  • M.J. Cohen 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)
  • K. Ley et al.

    Getting to the site of inflammation: the leukocyte adhesion cascade updated

    Nat Rev Immunol

    (2007)
  • M. van Meurs et al.

    Bench-to-bedside review: angiopoietin signalling in critical illness - a future target?

    Crit Care

    (2009)

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    This work was supported by HL 103836 and HL 088263 from the National Institutes of Health and an American Heart Association Established Investigator Award.

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