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A mouse is not a rat is not a man: species-specific metabolic responses to sepsis - a nail in the coffin of murine models for critical care research?

Year: 2013

Type: article

Abstract: Sepsis and consequent multi-organ failure are the leading causes of mortality in critically ill patients. Numerous therapeutic strategies, which yielded promising results in preclinical studies, have failed to show any efficacy in clinical trials. Historically, most of our (patho)physiological understanding of cardiovascular regulation in health and disease has been established in larger mammals, e.g., dog, pig, and sheep. However, a very large body of the literature collected over recent decades originates from investigations in rodents. Despite their small size, which makes surgery difficult and limits repetitive blood sampling, murine models have been widely used, not because they are more faithful to adult human pathophysiology than larger mammals but because they are inexpensive, easy to handle and care for, and with availability of gene knockout and overexpression strains. Investigators have performed studies without necessarily having a good appreciation of some fundamental differences in the physiology of rodents. These have been long established by comparative physiologists, yet have never been taught in any medical school. One can query the logic of inferring information on mechanisms involved in septic shock using species capable of decreasing their high resting metabolic rate both rapidly and massively, and with the associated circulatory and respiratory responses. Mouse models of acute inflammatory disorders have recently been questioned by Seok et al. [1] who found that “genomic responses to different acute inflammatory stresses are highly similar in humans”, whereas “these responses are not reproduced in current mouse models”. In this context, Zolfaghari et al. [2] compared the metabolic responses to polymicrobial sepsis in rats and mice. Their main findings were that mice presented with a progressive drop in whole body O2 uptake and a concurrent fall in body temperature, which was only partially restored by external warming. This marked metabolic depression coincided with pronounced impairment of left heart systolic contractility. In sharp contrast, only severely ill rats showed a comparably decreased cardiac output, and the metabolic depression was only present during the late premortem period. How can we explain these findings by Zolfaghari et al. [2]? The authors have the merit of raising an issue of crucial importance for critical care research, i.e., whether or

Source: Intensive Care Medicine Experimental

DOI: 10.1186/2197-425x-1-7

Authors: Peter Radermacher, Philippe Haouzi

Institutions: Universität Ulm, University Hospital Ulm, Pennsylvania State University, Penn State Milton S. Hershey Medical Center

Language: English

Topic: Sepsis Diagnosis and Treatment

Subfield: Epidemiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,890