Abandon the mouse research ship? Not just yet!

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 leukocytes 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 discuss valid limitations without overinterpretation. Hopefully, a balanced view of the strengths/weaknesses of using animals 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.

Fig. 1. Sources of inflammatory mediators produced in response to a critical condition

A typical critical illness, regardless whether of purely traumatic or infectious origin, triggers a broad inflammatory response that involves virtually all organ and cellular systems. The sum of inflammatory mediators circulating in the blood, the most expedient source of diagnostic information, is composed of proteins synthetized at multiple sites and sources. The simplified (given the overlap of cells and organs) schematic displays the most important and recognized sources of cytokine production. Black framing indicates the organ/cell populations which were used in the comparative genomic response study by Seok et al. (3). CNS: central nervous system.

Fig. 2. From DNA to the final product - Regulation of gene expression

The path from the genomic activation to the final protein is interrupted by a series of complex regulatory steps that may either completely halt and/or markedly modify the abundance of the final product. The simplified schematic lists the most important regulatory mechanisms between DNA activation and synthesis of the ready protein. 1) To initiate transcription, demethylated DNA must be bound to acetylated histones; 2) RNA-polymerase and transcription factors bind on DNA to start transcription; 3) mRNA leaves the nucleus and is translated into protein; 4) Some proteins are produced in a dormant state and require subsequent activation. Green arrow indicates the first regulatory step between genomic activation and generation of the corresponding mRNA. Red arrows indicate remaining regulatory steps prior to the emergence of the final protein coded by the mRNA.