Ensemble Models of Neutrophil Trafficking in Severe Sepsis

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 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. Author Summary: The pathophysiology of sepsis is complex and our mechanistic understanding remains incomplete. Mathematical models of the inflammatory response have been providing intellectual frameworks to reason about the complexity of sepsis. Due to an incompletely understood system along with very limited data, our approach focuses on building simplified, falsifiable and predictive models, and offers a means to quantify parametric uncertainty. Based on the construct that deterministic ensemble models exhibit population-like behavior, we developed a population-based computational framework that incorporates dysregulated neutrophil hyperactivity as a cellular dysfunction in septic processes. We hypothesize that probability distributions of physiological parameters conditional on population observations can characterize the range of possible physiologic responses in a population. Comparing the parameter ensembles from different phenotypes reveals some factors that play an important role in the expression of such phenotypes, such as sepsis survival. This framework can serve as an effective tool to gain insight into the pathophysiology of severe sepsis and generate testable hypotheses that guide future experiments. Our approach holds promise as a tool for integrating domain knowledge and experimental data into a quantitative assessment of population dynamics.