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High and Low Inflammatory Response Phenotypes in 101 Normal Human Subjects*

William Y. Park, MD; C. W. Frevert; V. A. Wong; T. R. Martin, MD, FCCP
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*From the Medical Research of the Seattle VA Medical Center and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA.

Correspondence to: William Y. Park, MD, Valley Internal Medicine, 4011 Talbot Rd South, 5th Floor, Renton, WA 90855



Chest. 2002;121(3_suppl):87S-88S. doi:10.1378/chest.121.3_suppl.87S
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%Abbreviations: IL = interleukin; VCAM = vascular cell adhesion molecule

Cytokine measurements in both BAL fluid and serum from patients with ARDS show a 10-fold to 100-fold difference. This variability likely explains why individual cytokines serve as poor prospective predictors of outcome in patients with ARDS and may partially explain why clinical trials of cytokine-directed inflammatory mediators largely have failed. Our goals were to determine the innate variability in the inflammatory response to a well-defined stimulus in healthy human whole blood and to identify patterns of cytokine production that correlate with high and low inflammatory response subsets of healthy subjects. An additional goal was to correlate these patterns with bioassays of net inflammation. Whole blood was obtained from healthy human volunteers (n = 101) and was stimulated with lipopolysaccharide (10 ng/mL) for 6 and 24 h at 37°C and 5% CO2. Cytokine expression was measured via enzyme-linked immunosorbent assay. Endothelial cell vascular cell adhesion molecule (VCAM)-1 expression and neutrophil chemotaxis were used as different measures of net inflammatory activity. Assays were repeated serially in a subset of subjects and results were consistent and reproducible over four weeks. Tumor necrosis factor-α, interleukin (IL)-6, IL-1β, IL-8, IL-1ra, IL-10, and monocyte chemoattractant protein-1 production varied 5-fold to 10-fold. The net inflammatory activity in plasma varied 3-fold to 10-fold, and neither VCAM-1 induction nor polymorphonuclear leukocyte chemotactic activity correlated with any single cytokine response. High and low responders were identified as having cytokine responses 1 to 2 SDs from the mean. The data demonstrate that a well-defined stimulus in whole-blood cultures can identify normal hosts with innate determinants that account for up to 10-fold variability in inflammatory responses in healthy individuals. This may be potentially useful in identifying subsets of healthy subjects for broader expression analysis, including gene arrays and proteomics, as well as for the focused study of polymorphisms and mutations in the genome. The data also show that measurements of single cytokines do not accurately predict the net inflammatory response in whole blood.

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