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A Neutrophil Phenotype Model for Extracorporeal Treatment of Sepsis

Malkin, AD and Sheehan, RP and Mathew, S and Federspiel, WJ and Redl, H and Clermont, G (2015) A Neutrophil Phenotype Model for Extracorporeal Treatment of Sepsis. PLoS Computational Biology, 11 (10). ISSN 1553-734X

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Malkin, ADalm270@pitt.eduALM270
Sheehan, RP
Mathew, Sshm82@pitt.eduSHM82
Federspiel, WJfederspielwj@pitt.eduWFEDERSP0000-0002-7068-6779
Redl, H
Clermont, Gcler@pitt.eduCLER0000-0002-0163-1379
ContributionContributors NameEmailPitt UsernameORCID
Centers: Other Centers, Institutes, Offices, or Units > McGowan Institute for Regenerative Medicine
Date: 1 January 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS Computational Biology
Volume: 11
Number: 10
DOI or Unique Handle: 10.1371/journal.pcbi.1004314
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Computational and Systems Biology
School of Medicine > Critical Care Medicine
School of Medicine > Surgery
Swanson School of Engineering > Bioengineering
Swanson School of Engineering > Chemical and Petroleum Engineering
Refereed: Yes
ISSN: 1553-734X
Date Deposited: 23 Aug 2016 13:44
Last Modified: 30 Mar 2021 13:56


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