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Mathematical modeling supports the presence of neutrophil depriming in vivo.


Type

Article

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Authors

Chilvers, Edwin R 
Peters, A Michael 

Abstract

Abstract Following migration into the intestinal mucosa in inflammatory bowel disease (IBD), neutrophils enter the intestinal lumen and are excreted. This provides a basis for quantification of disease activity by measuring excreted label following injection of In-111-labeled neutrophils. In severe pan-colitis, 50% of the injected In-111 is typically recovered in the feces, indicating that 50% of neutrophil turnover is via fecal excretion. Neutrophils have an intravascular lifespan of ~10 h and a distribution volume of ~10 L, so total body neutrophil turnover is 10.N/10 cells/h, where N is the peripheral blood neutrophil count (cells/L). Neutrophil loss via the colon in a patient with 50% fecal In-111 loss is therefore N/120 cells/min. Pan-colonic mucosal-blood flow in pan-colitis is 200 mL/min, which would deliver N/5 neutrophils to the colon per min. Therefore, 5/120, or 4%, of incoming neutrophils undergo migration into inflamed bowel. If the 96% of nonmigrating cells exit in a primed state, then at steady state >90% of circulating neutrophils would be primed if no depriming took place. As the highest level of priming seen in IBD is ~40%, this indicates that depriming within the circulation must take place. Using the above values in the steady state equation relating priming rate to depriming rate plus primed-cell destruction rate gives a mean depriming time of 35 min. We conclude that a very small proportion of neutrophils entering a site of inflammation migrate and that in vivo depriming must take place to limit the numbers of primed neutrophils in the circulation.

Description

Keywords

Depriming, inflammation, neutrophil, priming

Journal Title

Physiol Rep

Conference Name

Journal ISSN

2051-817X
2051-817X

Volume Title

2

Publisher

Wiley
Sponsorship
Academy of Medical Sciences (unknown)
Medical Research Council (MR/J00345X/1)
Wellcome Trust (101692/Z/13/Z)
This study was supported by the Wellcome Trust and the UK‐US Fulbright Commission; CS holds a Wellcome Trust Postdoctoral Clinical Research Fellowship and a Fulbright Scholar award. The work in the Chilvers lab is funded by the Wellcome Trust, MRC, Asthma‐UK, BBSRC, Gates Foundation and NIHR Cambridge BRC.