Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives

Lahoz-Beneytez, J., Elemans, M., Zhang, Y., Ahmed, Raya, Salam, A., Block, M., Niederalt, C., Asquith, B. and Macallan, D. 2016. Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives. Blood 127 (26) , pp. 3431-3438. 10.1182/blood-2016-03-700336

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Abstract

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 neutrophil precursors (R) to vary yielded a best-fit value of 0.19. Reanalysis of the previously published model and data also revealed the origin of their long estimates for neutrophil half-life: an implicit assumption that R is 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Society of Hematology
ISSN:	0006-4971
Date of Acceptance:	24 April 2016
Last Modified:	27 Mar 2020 02:34
URI:	https://orca.cardiff.ac.uk/id/eprint/102088

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