Lung Metabolic Activation as an Early Biomarker of Acute Respiratory Distress Syndrome and Local Gene Expression Heterogeneity.
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.



The authors produced ARDS in sheep with intravenous lipopolysaccharide (10 ng ⋅ kg ⋅ h) 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 NN-saline, and aeration using transmission scans. Species-specific microarray technology was used to assess regional gene expression.



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.



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.
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.).
Tyler J
TJ
Wellman
Nicolas
N
de Prost
Mauro
M
Tucci
Tilo
T
Winkler
Rebecca M
RM
Baron
Piotr
P
Filipczak
Benjamin
B
Raby
Jen-Hwa
JH
Chu
R Scott
RS
Harris
Guido
G
Musch
Luiz F
LF
Dos Reis Falcao
Vera
V
Capelozzi
Jose G
JG
Venegas
Marcos F
MF
Vidal Melo
D065767:Activation, Metabolic; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18; D015870:Gene Expression; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012128:Respiratory Distress Syndrome / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D012756:Sheep
D015415:Biomarkers; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18