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

Abstract

Human neutrophils have traditionally been thought to have a short half-life in blood; estimates vary from 4-18 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 deuteriumlabeled glucose (n=9), a compound with more rapid labeling kinetics. To interpret results we developed a novel mechanistic model. We applied this model to both previously-published (n=5) and newly-generated data. We initially constrained the ratio of the blood neutrophil pool to the marrow precursor pool (R=0.26, from published values). Analysis of heavy water datasets 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 transittime in the heavy water analysis gave a better-defined blood half-life, 0.77 ± 0.14 days (18.5 hours), close to glucose-derived values. Allowing R to vary yielded a best-fit value, R=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 one day.