title: Ensemble models of neutrophil trafficking in severe sepsis.
abstract: A hallmark of severe sepsis is systemic inflammation which activates leukocytes and can result in their misdirection. This leads to both impaired migration to the locus of infection and increased infiltration into healthy tissues. In order to better understand the pathophysiologic mechanisms involved, we developed a coarse-grained phenomenological model of the acute inflammatory response in CLP (cecal ligation and puncture)-induced sepsis in rats. This model incorporates distinct neutrophil kinetic responses to the inflammatory stimulus and the dynamic interactions between components of a compartmentalized inflammatory response. Ensembles of model parameter sets consistent with experimental observations were statistically generated using a Markov-Chain Monte Carlo sampling. Prediction uncertainty in the model states was quantified over the resulting ensemble parameter sets. Forward simulation of the parameter ensembles successfully captured experimental features and predicted that systemically activated circulating neutrophils display impaired migration to the tissue and neutrophil sequestration in the lung, consequently contributing to tissue damage and mortality. Principal component and multiple regression analyses of the parameter ensembles estimated from survivor and non-survivor cohorts provide insight into pathologic mechanisms dictating outcome in sepsis. Furthermore, the model was extended to incorporate hypothetical mechanisms by which immune modulation using extracorporeal blood purification results in improved outcome in septic rats. Simulations identified a sub-population (about 18% of the treated population) that benefited from blood purification. Survivors displayed enhanced neutrophil migration to tissue and reduced sequestration of lung neutrophils, contributing to improved outcome. The model ensemble presented herein provides a platform for generating and testing hypotheses in silico, as well as motivating further experimental studies to advance understanding of the complex biological response to severe infection, a problem of growing magnitude in humans.
authors.affiliation: CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. sas261@pitt.edu
authors.forename: Sang Ok
authors.initials: SO
authors.lastname: Song
authors.forename: Sang O K
authors.initials: SO
authors.lastname: Song
authors.forename: Justin
authors.initials: J
authors.lastname: Hogg
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Peng
authors.forename: Robert
authors.initials: R
authors.lastname: Parker
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
authors.forename: Gilles
authors.initials: G
authors.lastname: Clermont
mesh_terms: D000818:Animals; D003198:Computer Simulation; D007155:Immunologic Factors / Q000276:immunology*; D018448:Models, Immunological; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D051381:Rats; D018805:Sepsis / Q000276:immunology*; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology*
chemical_list: D007155:Immunologic Factors