Critical Care Medicine

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Critical Care Medicine:
doi: 10.1097/CCM.0000000000000222
Clinical Investigations

A Better Understanding of Why Murine Models of Trauma Do Not Recapitulate the Human Syndrome*

Gentile, Lori F. MD1; Nacionales, Dina C. MD1; Lopez, M. Cecilia BS2,3; Vanzant, Erin MD1; Cuenca, Angela MPH1; Cuenca, Alex G. MD, PhD1; Ungaro, Ricardo BS1; Baslanti, Tezcan Ozrazgat PhD4; McKinley, Bruce A. PhD1; Bihorac, Azra MD4; Cuschieri, Joseph MD5; Maier, Ronald V. MD5; Moore, Frederick A. MD1; Leeuwenburgh, Christiaan PhD6; Baker, Henry V. PhD1,2,3; Moldawer, Lyle L. PhD1; Efron, Philip A. MD1

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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.

Design: Preclinical controlled in vivo laboratory study and retrospective cohort study.

Setting: Laboratory of Inflammation Biology and Surgical Science and multi-institution level 1 trauma centers.

Subjects: 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.

Interventions: Mice underwent one of two severity polytrauma models of injury. Total blood leukocyte and neutrophil samples were collected.

Measurements and Main 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.

© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

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