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A Genome-Wide Expression Analysis in Blood Identifies Pre-Elafin as a Biomarker in ARDS

¹ Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts; ² Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts; and ³ Department of Medicine, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Zhaoxi Wang, M.D., Ph.D., 665 Huntington Avenue, I-1404B, Boston, MA 02115. E-mail: mikewang{at}hsph.harvard.edu

Previous microarray-based studies of acute respiratory distress syndrome (ARDS) were performed using various models to mimic disease pathogenesis. The complexity of the pathophysiologic response to direct or indirect lung injury in ARDS is difficult to reconstruct in experimental conditions. Thus, direct analysis of ARDS patient blood may provide valuable information. We investigated genome-wide gene expression profiles in paired whole blood samples from patients with ARDS (n = 8) during the acute stage (within 3 d of diagnosis) and recovery stage of ARDS (around ICU discharge). Among 126 differentially expressed genes, peptidase inhibitor 3 (PI3, encoding elafin, a potent neutrophil elastase inhibitor) had the largest fold-change (–3-fold changes, acute stage/recovery stage) in expression, indicating down-regulation during the acute stage of ARDS. We further examined plasma PI3 levels in 40 patients with ARDS and 23 at-risk control subjects from the same cohort. There was a coincidence of the microarray findings of lower PI3 gene expression with the lower plasma PI3 during the acute-stage. The plasma PI3 levels were statistically significant different among pre-diagnosis, day of diagnosis, and post-diagnosis groups (ANOVA, P = 0.001), with a trend of decreasing from pre- to post-diagnosis group. The time course of plasma PI3 decrease is well correlated with the course of early ARDS development (Pearson correlation coefficient: –0.52, P = 0.0006). Considering that PI3 can covalently binding to extracellular matrix in lung, circulating PI3 may provide a useful clinical marker for monitoring the early development of ARDS and may have implications for ARDS treatment.

Key Words: gene expression profiling • transcriptomics • acute respiratory distress syndrome • elafin • lung disease

CLINICAL RELEVANCE This study suggests a possible protective role of elafin (PI3) in acute respiratory distress syndrome (ARDS). Circulating PI3 may provide a useful clinical marker for monitoring the early development of ARDS and may have implications for ARDS treatment.