Ensemble Models of Neutrophil Trafficking in Severe Sepsis 英文参考文献.docVIP

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Ensemble Models of Neutrophil Trafficking in Severe Sepsis 英文参考文献.doc

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Ensemble Models of Neutrophil Trafficking in Severe Sepsis 英文参考文献

EnsembleModelsofNeutrophilTraffickinginSevere Sepsis SangO.K.Song1,2*,JustinHogg3,Zhi-YongPeng1,RobertParker2,JohnA.Kellum1,GillesClermont1 1CRISMA Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2Department of Chemical and PetroleumEngineering,UniversityofPittsburgh,Pittsburgh,Pennsylvania,UnitedStatesofAmerica,3DepartmentofComputationalandSystemsBiology,Universityof Pittsburgh,Pittsburgh,Pennsylvania,UnitedStatesofAmerica Abstract Ahallmarkofseveresepsisissystemicinflammationwhichactivatesleukocytesandcanresultintheirmisdirection.This leadstobothimpairedmigrationtothelocusofinfectionandincreasedinfiltrationintohealthytissues.Inordertobetter understandthepathophysiologicmechanismsinvolved,wedevelopedacoarse-grainedphenomenologicalmodelofthe acuteinflammatoryresponseinCLP(cecalligationandpuncture)-inducedsepsisinrats.Thismodelincorporatesdistinct neutrophil kinetic responses to the inflammatory stimulus and the dynamic interactions between components of a compartmentalizedinflammatoryresponse.Ensemblesofmodelparametersetsconsistentwithexperimentalobservations werestatistically generated usingaMarkov-ChainMonteCarlo sampling.Prediction uncertaintyin themodelstates was quantified over the resulting ensemble parameter sets. Forward simulation of the parameter ensembles successfully capturedexperimentalfeaturesandpredictedthatsystemicallyactivatedcirculatingneutrophilsdisplayimpairedmigration tothetissueandneutrophilsequestrationinthelung,consequentlycontributingtotissuedamageandmortality.Principal componentandmultipleregressionanalysesoftheparameterensemblesestimatedfromsurvivorandnon-survivorcohorts 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-populat