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Mathematical modeling supports the presence of neutrophil depriming in vivo.


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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.

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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.