Quantitative dynamics of in vivo bone marrow neutrophil production and egress in response to injury and infection

Abstract

Production rates of blood cells from the bone marrow (BM) can be determined from pool size and residence time in the circulation only during steady state. We describe a method to evaluate changes in BM neutrophil production following severe injury. Male CD-1 mice underwent nonlethal cutaneous burn injury, a lethal burn injury with Pseudomonas aeruginosa infection, or sham treatment, and received bromodeoxyuridine (BrdU) to label proliferative cells. Rates of BM neutrophil production and release into the circulation were determined using a mathematical model that integrates BM neutrophil pool size and fraction of BrdU labeled cells as a function of time. Absolute rates could not be quantified without BrdU data for the neutrophil progenitor pool; however, relative rates could be determined. BM neutrophil production and release significantly increased after injury. After nonlethal burn, release transiently exceeded production, causing a temporary decrease in BM neutrophil stores followed by reestablishment of a steady-state BM neutrophil pool similar to sham controls. After lethal burn infection, release always exceeded production, causing complete depletion of BM neutrophils and suppression of BM neutrophil production. This method is generally applicable to estimating production rates of nonproliferating, terminally differentiated cells, arising from a stem cell pool in vivo.