Review Article ABANDON THE MOUSE RESEARCH SHIP? NOT JUST YET! Marcin F. Osuchowski,* Daniel G. Remick, † James A. Lederer, ‡ Charles H. Lang, § Ansgar O. Aasen, || Mayuki Aibiki, ¶ Luciano C. Azevedo,** Soheyl Bahrami,* Mihaly Boros, †† Robert Cooney, ‡‡ Salvatore Cuzzocrea, §§ Yong Jiang, |||| Wolfgang G. Junger, ¶¶ Hiroyuki Hirasawa,*** Richard S. Hotchkiss, ††† Xiang-An Li, ‡‡‡ Peter Radermacher, §§§ Heinz Redl,* Reinaldo Salomao, |||||| Amin Soebandrio, ¶¶¶ Christoph Thiemermann,**** Jean-Louis Vincent, †††† Peter Ward, ‡‡‡‡ Yong-Ming Yao, §§§§ Huang-Ping Yu, |||||||| Basilia Zingarelli, ¶¶¶¶ and Irshad H. Chaudry***** *Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria; † Boston University School of Medicine and ‡ Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; § Pennsylvania State College of Medicine, Hershey, Pennsylvania; || Oslo University Hospital, Oslo, Norway; ¶ Ehime University, Matsuyama, Japan; **Research and Education Institute, Hospital Sirio-Libanes, Sa ˜ o Paulo, Brazil; †† Institute of Surgical Research, University of Szeged, Szeged, Hungary; ‡‡ State University of New York Upstate Medical University, Syracuse, New York; §§ Department of Biological and Environmental Sciences, University of Messina, Messina, Italy; |||| Southern Medical University Guangzhou, Guangzhou, China; ¶¶ Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; ***Chiba University Graduate School of Medicine, Chiba, Japan; ††† Washington University School of Medicine, St Louis, Missouri; ‡‡‡ University of Kentucky College of Medicine, Lexington, Kentucky; §§§ Ulm Medical University Clinic, Ulm, Germany; |||||| Division of Infectious Diseases, Department of Medicine, Hospital Sa ˜ o PauloYEscola Paulista de Medicina, Federal University of Sa ˜ o Paulo, Sao Paulo, Brazil; ¶¶¶ University of Indonesia, Jakarta, Indonesia;****The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; †††† University of Brussels, Erasme University Hospital, Brussels, Belgium; ‡‡‡‡ The University of Michigan Medical School, Ann Arbor, Michigan; §§§§ Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China; |||||||| Chang Gung Memorial Hospital, Taipei, Taiwan; ¶¶¶¶ Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; and *****University of Alabama at Birmingham, Birmingham, Alabama Received 9 Dec 2013; first review completed 26 Dec 2013; accepted in final form 11 Feb 2014 ABSTRACT—Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiologic alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently, the lay press severely criticized the translational relevance of mouse models in critical care medicine. A series of provocative editorials were elicited by a highly publicized research report in the Proceedings of the National Academy of Sciences (PNAS; February 2013), which identified an unrecognized gene expression profile mismatch between human and murine leuko- cytes following burn/trauma/endotoxemia. Based on their data, the authors concluded that mouse models of trauma/ inflammation are unsuitable for studying corresponding human conditions. We believe this conclusion was not justified. In conjunction with resulting negative commentary in the popular press, it can seriously jeopardize future basic research in critical care medicine. We will address some limitations of that PNAS report to provide a framework for discussing its conclusions and attempt to present a balanced summary of strengths/weaknesses of use of mouse models. While many investigators agree that animal research is a central component for improved patient outcomes, it is important to acknowledge known limitations in clinical translation from mouse to man. The scientific community is responsible to dis- cuss valid limitations without overinterpretation. Hopefully, a balanced view of the strengths/weaknesses of using ani- mals for trauma/endotoxemia/critical care research will not result in hasty discount of the clear need for using animals to advance treatment of critically ill patients. KEYWORDS—Mouse models of critical illness, trauma, endotoxemia, sepsis, burn Extraordinary claims require extraordinary evidence. VCarl Sagan INTRODUCTION In the United States (1) and European Union countries (2), approximately 15 and 7 million laboratory rodents, respec- tively, are used annually for research and testing. While it is difficult to precisely define the exact number of mice used in the field of critical care illnesses (such as trauma, burn, in- fections, endotoxemia, and sepsis), it is not an overstatement that the majority of preclinical studies rely on this species. As 1 SHOCK, Vol. 00, No. 00, pp. 00Y00, 2014 Address reprint requests to Marcin F. Osuchowski, DVM, PhD, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstrasse 13A- 1200 Vienna, Austria. E-mail: marcin.osuchowski@trauma.lbg.ac.at. Co-correspondence: Irshad H. Chaudry, PhD, Center for Surgical Research, University of Alabama at Birmingham, G094 Volker Hall, 1670 University Blvd, Birmingham, AL 35294. E-mail: Ichaudry@uab.edu. The authors declare that no competing interests exist. DOI: 10.1097/SHK.0000000000000153 Copyright Ó 2014 by the Shock Society