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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

doi: 10.1097/CCM.0000000000000222
Clinical Investigations

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.

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.

* See also p. 1552.

Dr. Gentile contributed to the analysis of data, conception, design, composition, drafting, and editing of the manuscript. Dr. Nacionales performed animal experiments, data collection, and contributed to the editing of the manuscript. Ms. Lopez contributed to the analysis of data and editing of the manuscript. Dr. Vanzant, Ms. Cuenca, Dr. G. Cuenca, Dr. McKinley, and Dr. Moore contributed to the manuscript editing. Mr. Ungaro contributed animal experiments and laboratory data collection and to the editing of the manuscript. Dr. Baslanti contributed to the editing of the manuscript. Drs. Bihorac and Leeuwenburgh contributed to the design and editing of the manuscript. Drs. Cuschieri and Maier contributed to the conception and design of the manuscript and the editing of the manuscript. Drs. Baker and Moldawer contributed to the conception and design of the manuscript and the composition/editing of the manuscript. Dr. Efron contributed to the analysis of data, conception, design, composition, drafting, and editing of the manuscript.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by grants R01 GM-40586-24 and R01 GM-80576-06 from the National Institute of General Medical Sciences (NIGMS) and also by grant NIH/NIA P30AG028740 from the Claude D. Pepper Older Americans Independence Center. This work was also supported by a contract (U54 GM-062119-10) awarded by the NIGMS to Dr. Ronald Tompkins, Massachusetts General Hospital, and represents a secondary use of the Trauma Related Database developed by that Program. However, the results and conclusions contained in the manuscript have not necessarily been reviewed by the program and do not necessarily represent the views of the Glue Grant Program or the NIGMS.

Dr. Gentile received support for article research from the National Institutes of Health (NIH) and was supported by a T32 training grant (T32 GM-008721-13) in burns and trauma from the National Institute of General Medical Sciences (NIGMS). Ms. Lopez’s institution received grant support. Dr. G. Cuenca was supported by a T32 training grant (T32 GM-008721-13) in burns and trauma from the NIGMS. Dr. Bihorac received support for article research from NIH (K23 GM-087709 Azra). She and her institution received grant support from NIH and Astute Medical. Dr. Cuschieri received support for article research from NIH. Dr. Maier received support for article research from NIH. His institution received grant support. Dr. Moore received support for article research from NIH. His institution received grant support. Dr. Leeuwenburgh received support for article research from NIH. His institution received grant support from the University of Florida. Dr. Baker’s institution received grant support from NIH. Dr. Moldawer received support for article research from NIH. His institution received grant support from NIH. Dr. Efron received support for article research from NIH (U54 GM-062119-10). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: philip.efron@surgery.ufl.edu

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