Modeling Neutrophil Dynamics in Sepsis and Cancer Treatment

A mathematical model of neutrophil and granulocyte colony stimulating factor (G-CSF) dynamics is developed to capture the response of circulating neutrophil levels to inflammatory and anticancer drug challenges. Severe infection or trauma induces inflammation, leading to: (i) the recruitment of neutrophils to the site of infection; (ii) misdirected neutrophil recruitment to healthy tissue, which causes damage; and (iii) an increase in neutrophil production through the G-CSF signaling cascade. The limiting element of cancer chemotherapy is often toxicity. Some drugs kill neutrophil precursor cells, leading to a decrease in the absolute neutrophil count in blood. Starting from the 6 compartment model of Friberg et al. (2002), the model is extended to capture neutrophil and G-CSF dynamics in response to both inflammation and chemotherapy using lipopolysaccharide (inflammatory) and docetaxel (chemotherapy) response data. As a more complex inflammatory challenge, cecal ligation and puncture (CLP) is simulated, and the model is consistent with neutrophil and G-CSF data from the literature. The expanded biology in this model provides a superior structure for use in designing and evaluating treatments aimed at modulating neutrophil dynamics in severe infections.