Critical Care Medicine  |   November 2016
Lung Metabolic Activation as an Early Biomarker of Acute Respiratory Distress Syndrome and Local Gene Expression Heterogeneity
Author Notes
  • From the Departments of Anesthesia, Critical Care and Pain Medicine (T.J.W., M.T., T.W., G.M., L.F.d.R.F., J.G.V., M.F.V.M.) and Medicine (Pulmonary and Critical Care; R.S.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Medical Intensive Care Unit, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, France (N.d.P.); Department of Medicine (Pulmonary and Critical Care) (R.M.B., P.F.) and Channing Laboratory (B.R., J.-h.C.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and Laboratory of Histomorphometry and Lung Genomics, University of Sao Paulo, Sao Paulo, Brazil (V.C.).
  • Submitted for publication December 5, 2015. Accepted for publication June 27, 2016.
    Submitted for publication December 5, 2015. Accepted for publication June 27, 2016.×
  • This article is featured in “This Month in Anesthesiology,” page 1A.
    This article is featured in “This Month in Anesthesiology,” page 1A.×
  • Corresponding article on page 838.
    Corresponding article on page 838.×
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    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Address correspondence to Dr. Vidal Melo: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. VidalMelo.Marcos@mgh.harvard.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Critical Care / Infectious Disease / Respiratory System
Critical Care Medicine   |   November 2016
Lung Metabolic Activation as an Early Biomarker of Acute Respiratory Distress Syndrome and Local Gene Expression Heterogeneity
Anesthesiology 11 2016, Vol.125, 992-1004. doi:10.1097/ALN.0000000000001334
Anesthesiology 11 2016, Vol.125, 992-1004. doi:10.1097/ALN.0000000000001334
Abstract

Background: Acute respiratory distress syndrome (ARDS) is an inflammatory condition comprising diffuse lung edema and alveolar damage. ARDS frequently results from regional injury mechanisms. However, it is unknown whether detectable inflammation precedes lung edema and opacification and whether topographically differential gene expression consistent with heterogeneous injury occurs in early ARDS. The authors aimed to determine the temporal relationship between pulmonary metabolic activation and density in a large animal model of early ARDS and to assess gene expression in differentially activated regions.

Methods: The authors produced ARDS in sheep with intravenous lipopolysaccharide (10 ng ⋅ kg−1 ⋅ h−1) and mechanical ventilation for 20 h. Using positron emission tomography, the authors assessed regional cellular metabolic activation with 2-deoxy-2-[(18)F]fluoro-d-glucose, perfusion and ventilation with 13NN-saline, and aeration using transmission scans. Species-specific microarray technology was used to assess regional gene expression.

Results: Metabolic activation preceded detectable increases in lung density (as required for clinical diagnosis) and correlated with subsequent histologic injury, suggesting its predictive value for severity of disease progression. Local time courses of metabolic activation varied, with highly perfused and less aerated dependent lung regions activated earlier than nondependent regions. These regions of distinct metabolic trajectories demonstrated differential gene expression for known and potential novel candidates for ARDS pathogenesis.

Conclusions: Heterogeneous lung metabolic activation precedes increases in lung density in the development of ARDS due to endotoxemia and mechanical ventilation. Local differential gene expression occurs in these early stages and reveals molecular pathways relevant to ARDS biology and of potential use as treatment targets.