title: Interleukin-6 infusion blunts proinflammatory cytokine production without causing systematic toxicity in a swine model of uncontrolled hemorrhagic shock.
abstract: BACKGROUND
  Serum elevations of interleukin-6 (IL-6) correlate with multiple organ dysfunction syndrome and mortality in critically injured trauma patients. Data from rodent models of controlled hemorrhage suggest that recombinant IL-6 (rIL-6) infusion protects tissue at risk for ischemia-reperfusion injury. Exogenous rIL-6 administered during shock appears to abrogate inflammation, providing a protective rather than a deleterious influence. In an examination of this paradox, the current study aimed to determine whether rIL-6 decreases inflammation in a clinically relevant large animal model of uncontrolled hemorrhagic shock, (UHS), and to investigate the mechanism of protection.
  
  
  METHODS
  Swine were randomized to four groups (8 animals in each): (1) sacrifice, (2) sham (splenectomy followed by hemodilution and cooling to 33 degrees C), (3) rIL-6 infusion (sham plus UHS using grade 5 liver injury with packing and resuscitation plus blinded infusion of rIL-6 [10 mcg/kg]), and (4) placebo (UHS plus blinded vehicle). After 4 hours, blood was sampled, estimated blood loss determined, animals sacrificed, and lung harvested for RNA isolation. Quantitative reverse transcriptase-polymerase chain reaction was used to assess granulocyte colony-stimulating factor (G-CSF), IL-6, and tumor necrosis factor-alpha (TNFalpha) messenger ribonucleic acid (mRNA) levels. Serum levels of IL-6 and TNFalpha were measured by enzyme-linked immunoassay (ELISA).
  
  
  RESULTS
  As compared with placebo, IL-6 infusion in UHS did not increase estimated blood loss or white blood cell counts, nor decrease hematocrit or platelet levels. As compared with the sham condition, lung G-CSF mRNA production in UHS plus placebo increased eightfold (*p < 0.05). In contrast, rIL-6 infusion plus UHS blunted G-CSF mRNA levels, which were not significantly higher than sham levels (p = 0.1). Infusion of rIL-6 did not significantly affect endogenous production of either lung IL-6 or mRNA. As determined by ELISA, rIL-6 infusion did not increase final serum levels of IL-6 or TNFalpha over those of sham and placebo conditions.
  
  
  CONCLUSIONS
  Exogenous rIL-6 blunts lung mRNA levels of the proinflammatory cytokine G-CSF. The administration of rIL-6 does not increase the local expression of IL-6 nor TNFalpha mRNA in the lung. Additionally, rIL-6 infusion does not appear to cause systemic toxicity.
authors.affiliation: Department of Surgery, Stanford University Medical Center, Palo Alto, California 94305, USA. sbrundage@stanford.edu
authors.forename: Susan I
authors.initials: SI
authors.lastname: Brundage
authors.forename: N A
authors.initials: NA
authors.lastname: Zautke
authors.forename: J B
authors.initials: JB
authors.lastname: Holcomb
authors.forename: D A
authors.initials: DA
authors.lastname: Spain
authors.forename: J C
authors.initials: JC
authors.lastname: Lam
authors.forename: M A
authors.initials: MA
authors.lastname: Mastrangelo
authors.forename: J M
authors.initials: JM
authors.lastname: Macaitis
authors.forename: D J
authors.initials: DJ
authors.lastname: Tweardy
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000008:administration & dosage* / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D010919:Placebos; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D011994:Recombinant Proteins / Q000008:administration & dosage; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012771:Shock, Hemorrhagic / Q000378:metabolism / Q000517:prevention & control*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D010919:Placebos; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor