title: A Neutrophil Phenotype Model for Extracorporeal Treatment of Sepsis.
abstract: Neutrophils play a central role in eliminating bacterial pathogens, but may also contribute to end-organ damage in sepsis. Interleukin-8 (IL-8), a key modulator of neutrophil function, signals through neutrophil specific surface receptors CXCR-1 and CXCR-2. In this study a mechanistic computational model was used to evaluate and deploy an extracorporeal sepsis treatment which modulates CXCR-1/2 levels. First, a simplified mechanistic computational model of IL-8 mediated activation of CXCR-1/2 receptors was developed, containing 16 ODEs and 43 parameters. Receptor level dynamics and systemic parameters were coupled with multiple neutrophil phenotypes to generate dynamic populations of activated neutrophils which reduce pathogen load, and/or primed neutrophils which cause adverse tissue damage when misdirected. The mathematical model was calibrated using experimental data from baboons administered a two-hour infusion of E coli and followed for a maximum of 28 days. Ensembles of parameters were generated using a Bayesian parallel tempering approach to produce model fits that could recreate experimental outcomes. Stepwise logistic regression identified seven model parameters as key determinants of mortality. Sensitivity analysis showed that parameters controlling the level of killer cell neutrophils affected the overall systemic damage of individuals. To evaluate rescue strategies and provide probabilistic predictions of their impact on mortality, time of onset, duration, and capture efficacy of an extracorporeal device that modulated neutrophil phenotype were explored. Our findings suggest that interventions aiming to modulate phenotypic composition are time sensitive. When introduced between 3-6 hours of infection for a 72 hour duration, the survivor population increased from 31% to 40-80%. Treatment efficacy quickly diminishes if not introduced within 15 hours of infection. Significant harm is possible with treatment durations ranging from 5-24 hours, which may reduce survival to 13%. In severe sepsis, an extracorporeal treatment which modulates CXCR-1/2 levels has therapeutic potential, but also potential for harm. Further development of the computational model will help guide optimal device development and determine which patient populations should be targeted by treatment.
authors.affiliation: McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Malkin
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Sheehan
authors.affiliation: Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Shibin
authors.initials: S
authors.lastname: Mathew
authors.affiliation: McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Federspiel
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA center, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
authors.affiliation: CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Gilles
authors.initials: G
authors.lastname: Clermont
mesh_terms: D000818:Animals; D001781:Blood Component Removal / Q000379:methods / Q000401:mortality; D003198:Computer Simulation; D005112:Extracorporeal Circulation / Q000379:methods* / Q000401:mortality; D018448:Models, Immunological; D009504:Neutrophils / Q000145:classification / Q000276:immunology*; D010215:Papio; D011379:Prognosis; D054387:Receptors, CXCR / Q000276:immunology* / Q000302:isolation & purification; D023062:Receptors, Interleukin-8A / Q000276:immunology / Q000302:isolation & purification; D023063:Receptors, Interleukin-8B / Q000276:immunology / Q000302:isolation & purification; D018805:Sepsis / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D054387:Receptors, CXCR; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B