title: A better understanding of why murine models of trauma do not recapitulate the human syndrome.
abstract: OBJECTIVE
  Genomic analyses from blood leukocytes have concluded that mouse injury poorly reflects human trauma at the leukocyte transcriptome. Concerns have focused on the modest severity of murine injury models, differences in murine compared with human age, dissimilar circulating leukocyte populations between species, and whether similar signaling pathways are involved. We sought to examine whether the transcriptomic response to severe trauma in mice could be explained by these extrinsic factors, by utilizing an increasing severity of murine trauma and shock in young and aged mice over time, and by examining the response in isolated neutrophil populations.
  
  
  METHODS
  Preclinical controlled in vivo laboratory study and retrospective cohort study.
  
  
  METHODS
  Laboratory of Inflammation Biology and Surgical Science and multi-institution level 1 trauma centers.
  
  
  METHODS
  Six- to 10-week-old and 20- to 24-month-old C57BL/6 (B6) mice and two cohorts of 167 and 244 severely traumatized (Injury Severity Score > 15) adult (> 18 yr) patients.
  
  
  METHODS
  Mice underwent one of two severity polytrauma models of injury. Total blood leukocyte and neutrophil samples were collected.
  
  
  RESULTS
  Fold expression changes in leukocyte and neutrophil genome-wide expression analyses between healthy and injured mice (p < 0.001) were compared with human total and enriched blood leukocyte expression analyses of severe trauma patients at 0.5, 1, 4, 7, 14, and 28 days after injury (Glue Grant trauma-related database). We found that increasing the severity of the murine trauma model only modestly improved the correlation in the transcriptomic response with humans, whereas the age of the mice did not. In addition, the genome-wide response to blood neutrophils (rather than total WBC) was also not well correlated between humans and mice. However, the expression of many individual gene families was much more strongly correlated after injury in mice and humans.
  
  
  CONCLUSIONS
  Although overall transcriptomic association remained weak even after adjusting for the severity of injury, age of the animals, timing, and individual leukocyte populations, there were individual signaling pathways and ontogenies that were strongly correlated between mice and humans. These genes are involved in early inflammation and innate/adaptive immunity.
authors.affiliation: 1Department of Surgery, University of Florida College of Medicine, Gainesville, FL. 2Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL. 3University of Florida Genetics Institute, University of Florida College of Medicine, Gainesville, FL. 4Department of Anesthesia, University of Florida College of Medicine, Gainesville, FL. 5Department of Surgery, Harborview Medical Center, University of Washington, Seattle, WA. 6Institute on Aging, Division of Biology of Aging, University of Florida College of Medicine, Gainesville, FL.
authors.forename: Lori F
authors.initials: LF
authors.lastname: Gentile
authors.forename: Dina C
authors.initials: DC
authors.lastname: Nacionales
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Lopez
authors.forename: Erin
authors.initials: E
authors.lastname: Vanzant
authors.forename: Angela
authors.initials: A
authors.lastname: Cuenca
authors.forename: Alex G
authors.initials: AG
authors.lastname: Cuenca
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ungaro
authors.forename: Tezcan Ozrazgat
authors.initials: TO
authors.lastname: Baslanti
authors.forename: Bruce A
authors.initials: BA
authors.lastname: McKinley
authors.forename: Azra
authors.initials: A
authors.lastname: Bihorac
authors.forename: Joseph
authors.initials: J
authors.lastname: Cuschieri
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Maier
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Moore
authors.forename: Christiaan
authors.initials: C
authors.lastname: Leeuwenburgh
authors.forename: Henry V
authors.initials: HV
authors.lastname: Baker
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: Philip A
authors.initials: PA
authors.lastname: Efron
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D015601:Injury Severity Score; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D012189:Retrospective Studies; D059467:Transcriptome / Q000502:physiology; D014193:Trauma Centers; D014949:Wounds, Nonpenetrating / Q000235:genetics / Q000378:metabolism* / Q000473:pathology