title: A two-compartment mathematical model of endotoxin-induced inflammatory and physiologic alterations in swine.
abstract: OBJECTIVE
  To gain insights into individual variations in acute inflammation and physiology.
  
  
  METHODS
  Large-animal study combined with mathematical modeling.
  
  
  METHODS
  Academic large-animal and computational laboratories.
  
  
  METHODS
  Outbred juvenile swine.
  
  
  METHODS
  Four swine were instrumented and subjected to endotoxemia (100 µg/kg), followed by serial plasma sampling.
  
  
  RESULTS
  Swine exhibited various degrees of inflammation and acute lung injury, including one death with severe acute lung injury (PaO(2)/FIO(2) ratio μ200 and static compliance μ10 L/cm H(2)O). Plasma interleukin-1β, interleukin-4, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-α, high mobility group box-1, and NO(2)/NO(3) were significantly (p μ .05) elevated over the course of the experiment. Principal component analysis was used to suggest principal drivers of inflammation. Based in part on principal component analysis, an ordinary differential equation model was constructed, consisting of the lung and the blood (as a surrogate for the rest of the body), in which endotoxin induces tumor necrosis factor-α in monocytes in the blood, followed by the trafficking of these cells into the lung leading to the release of high mobility group box-1, which in turn stimulates the release of interleukin-1β from resident macrophages. The ordinary differential equation model also included blood pressure, PaO(2), and FIO(2), and a damage variable that summarizes the health of the animal. This ordinary differential equation model could be fit to both inflammatory and physiologic data in the individual swine. The predicted time course of damage could be matched to the oxygen index in three of the four swine.
  
  
  CONCLUSIONS
  The approach described herein may aid in predicting inflammation and physiologic dysfunction in small cohorts of subjects with diverse phenotypes and outcomes.
authors.affiliation: Department of Surgery, Upstate Medical University, Syracuse, NY, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Nieman
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: Joydeep
authors.initials: J
authors.lastname: Sarkar
authors.forename: Brian
authors.initials: B
authors.lastname: Kubiak
authors.forename: Cordelia
authors.initials: C
authors.lastname: Ziraldo
authors.forename: Joyeeta
authors.initials: J
authors.lastname: Dutta-Moscato
authors.forename: Christopher
authors.initials: C
authors.lastname: Vieau
authors.forename: Derek
authors.initials: D
authors.lastname: Barclay
authors.forename: Louis
authors.initials: L
authors.lastname: Gatto
authors.forename: Kristopher
authors.initials: K
authors.lastname: Maier
authors.forename: Gregory
authors.initials: G
authors.lastname: Constantine
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Ruben
authors.initials: R
authors.lastname: Zamora
authors.forename: Qi
authors.initials: Q
authors.lastname: Mi
authors.forename: Steve
authors.initials: S
authors.lastname: Chang
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000503:physiopathology; D000818:Animals; D019446:Endotoxemia / Q000139:chemically induced / Q000503:physiopathology; D004731:Endotoxins / Q000494:pharmacology; D005260:Female; D024243:HMGB1 Protein / Q000097:blood; D006439:Hemodynamics / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D016753:Interleukin-10 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008954:Models, Biological; D025341:Principal Component Analysis; D012143:Respiratory Physiological Phenomena; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D004731:Endotoxins; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4