Inflammation following traumatic brain injury in humans: Insights from data-driven and mechanistic models into survival and death

Andrew Abboud, Qi Mi, Ava Puccio, David Okonkwo, Marius Buliga, Gregory Constantine, Yoram Vodovotz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Inflammation induced by traumatic brain injury (TBI) is a complex mediator of morbidity and mortality. We have previously demonstrated the utility of both data-driven and mechanistic models in settings of traumatic injury. We hypothesized that differential dynamic inflammation programs characterize TBI survivors vs. non-survivors, and sought to leverage computational modeling to derive novel insights into this life/death bifurcation. Thirteen inflammatory cytokines and chemokines were determined using Luminex™ in serial cerebrospinal fluid (CSF) samples from 31 TBI patients over 5 days. In this cohort, 5 were non-survivors (Glasgow Outcome Scale [GOS] score = 1) and 26 were survivors (GOS > 1). A Pearson correlation analysis of initial injury (Glasgow Coma Scale [GCS]) vs. GOS suggested that survivors and non-survivors had distinct clinical response trajectories to injury. Statistically significant differences in interleukin (IL)-4, IL-5, IL-6, IL-8, IL-13, and tumor necrosis factor-α (TNF-α) were observed between TBI survivors vs. non-survivors over 5 days. Principal Component Analysis and Dynamic Bayesian Network inference suggested differential roles of chemokines, TNF-α, IL-6, and IL-10, based upon which an ordinary differential equation model of TBI was generated. This model was calibrated separately to the time course data of TBI survivors vs. non-survivors as a function of initial GCS. Analysis of parameter values in ensembles of simulations from these models suggested differences in microglial and damage responses in TBI survivors vs. non-survivors. These studies suggest the utility of combined data-driven and mechanistic models in the context of human TBI.

Original languageEnglish
Article number342
JournalFrontiers in Pharmacology
Volume7
Issue numberSEP
DOIs
StatePublished - 27 Sep 2016
Externally publishedYes

Keywords

  • Data-driven modeling
  • Inflammation
  • Inflammatory mediators in CNS
  • Mathematical modeling
  • Mortality
  • TBI outcome

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