Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives
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Supporting information
Accepted version
Author(s)
Type
Journal Article
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.
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.
Date Issued
2016-06-30
Date Acceptance
2016-04-24
Citation
Blood, 2016, 127 (26), pp.3431-3438
ISSN
0006-4971
Publisher
American Society of Hematology
Start Page
3431
End Page
3438
Journal / Book Title
Blood
Volume
127
Issue
26
Copyright Statement
This is a closed deposit for REF purposes only. This article will not be available to the public in this repository as per the publisher's policy outlined at http://www.bloodjournal.org/page/authors/copyright-information
Sponsor
Commission of the European Communities
LEUKAEMIA & LYMPHOMA RESEARCH
Bloodwise (formerly LLR)
Wellcome Trust
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Identifier
https://ashpublications.org/blood/article/127/26/3431/35369/Human-neutrophil-kinetics-modeling-of-stable
Grant Number
317040
15012
15012
103865/Z/14/Z
12345-11
G0601072
MR/J007439/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Hematology
COLONY-STIMULATING FACTOR
HUMAN BONE-MARROW
IN-VIVO
CELL-PROLIFERATION
DNA
CELLULARITY
MATURATION
CLEARANCE
MOUSE
RATES
Adult
Deuterium
Female
Glucose
Granulocyte Precursor Cells
Half-Life
Humans
Isotope Labeling
Kinetics
Male
Middle Aged
Models, Biological
Neutrophils
Neutrophils
Granulocyte Precursor Cells
Humans
Deuterium
Glucose
Isotope Labeling
Kinetics
Models, Biological
Half-Life
Adult
Middle Aged
Female
Male
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
Immunology
Publication Status
Published
Date Publish Online
2016-05-02