Journal
BLOOD
Volume 127, Issue 26, Pages 3431-3438Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-03-700336
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Funding
- Medical Research Council UK [J007439, G1001052]
- European Union [317040]
- Leukemia and Lymphoma Research [15012]
- MRC [G0601072, MR/J007439/1, G1001052] Funding Source: UKRI
- Wellcome Trust [103865/Z/14/Z] Funding Source: Wellcome Trust
- Medical Research Council [MR/J007439/1, G1001052, G0601072] Funding Source: researchfish
- Wellcome Trust [103865/Z/14/Z] Funding Source: researchfish
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Human neutrophils have traditionally been thought to have a short half-life in blood; estimates vary from 4 to 18 hours. This dogma was recently challenged by stable isotope labeling studies with heavy water, which yielded estimates in excess of 3 days. To investigate this disparity, we generated new stable isotope labeling data in healthy adult subjects using both heavy water (n = 4) and deuterium-labeled glucose (n = 9), a compound with more rapid labeling kinetics. To interpret results, we developed a novel mechanistic model and applied it to previously published (n = 5) and newly generated data. We initially constrained the ratio of the blood neutrophil pool to the marrow precursor pool (ratio = 0.26; from published values). Analysis of heavy water data sets yielded turnover rates consistent with a short blood half-life, but parameters, particularly marrow transit time, were poorly defined. Analysis of glucose-labeling data yielded more precise estimates of half-life (0.79 +/- 0.25 days; 19 hours) and marrow transit time (5.80 +/- 0.42 days). Substitution of this marrow transit time in the heavy water analysis gave a better-defined blood half-life of 0.77 +/- 0.14 days (18.5 hours), close to glucose-derived values. Allowing the ratio of blood neutrophils to mitotic neutrophilprecursors (R) to vary yieldedabest-fit valueof 0.19. Reanalysisof the previouslypublishedmodelanddata also revealed theorigin of their longestimates forneutrophilhalf-life: animplicitassumptionthatRis very large, which is physiologically untenable. We conclude that stable isotope labeling in healthy humans is consistent with a blood neutrophil half-life of less than 1 day.
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