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

• Published in: Blood Vol. 127; no. 26; pp. 3431 - 3438
• Main Authors: Lahoz-Beneytez, Julio, Elemans, Marjet, Zhang, Yan, Ahmed, Raya, Salam, Arafa, Block, Michael, Niederalt, Christoph, Asquith, Becca, Macallan, Derek
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.06.2016; American Society of Hematology
• Subjects: Adult; Deuterium - chemistry; Female; Glucose - chemistry; Glucose - metabolism; Glucose - pharmacology; Granulocyte Precursor Cells - cytology; Granulocyte Precursor Cells - metabolism; Half-Life; Humans; Isotope Labeling - methods; Kinetics; Male; Middle Aged; Models, Biological; Neutrophils - cytology; Neutrophils - metabolism; Phagocytes, Granulocytes, and Myelopoiesis
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2016-03-700336

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. •Mechanistic modeling of stable isotope labeling verifies human neutrophil half-lives of 13-19 h in contrast to recent estimates of >3 days.•Human neutrophil kinetics can be measured using a single-dose deuterium-labeled glucose protocol.