Genomic responses in mouse models poorly mimic human inflammatory diseases
Murine models have been extensively used in recent decades to identify and test drug candidates for subsequent human trials (1–3). However, few of these human trials have shown success (4–7). The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed (8–11). Despite commentaries that question the merit of an overreliance of animal systems to model human immunology (3, 12, 13), in the absence of systematic evidence, investigators and public regulators assume that results from animal research reflect human disease. To date, there have been no studies to systematically evaluate, on a molecular basis, how well the murine clinical models mimic human inflammatory diseases in patients. The Inflammation and Host Response to Injury, Large Scale Collaborative Research Program has completed multiple studies on the genomic responses to systemic inflammation in patients and human volunteers as well as murine models (14–18). These datasets include genome-wide expression analysis on white blood cells obtained from serial blood draws in 167 patients up to 28 d after severe blunt trauma (15), 244 patients up to 1 y after burn injury, and 4 healthy humans for 24 h after administration of low-dose bacterial endotoxin (14) and expression analysis on analogous samples from well-established mouse models of trauma, burns, and endotoxemia (16 treated and 16 controls per model) (16–18). In humans, severe inflammatory stress produces a genomic storm affecting all major cellular functions and pathways (15) and therefore, provided sufficient perturbations to allow comparisons between the genes in the human conditions and their orthologs in the murine models. In this article, we report on a systematic comparison of the genomic response between human inflammatory diseases andmurine models. First, we compared the correlations of gene expression changes with trauma, burns, and endotoxemia between human subjects and corresponding mouse models. Second, we characterized and compared the temporal gene response patterns seen in these human conditions and models. Third, we also identified the major signaling pathways significantly regulated in the inflammatory response to human injuries and compared them with the human in vivo endotoxemia model and three murine models. Fourth, we sought and evaluated representative patient and murine studies of several additional acute inflammatory diseases. These results show that the genomic responses to different acute inflammatory stresses are highly similar in humans, but these responses are not reproduced in the current mouse models. New approaches need be explored to improve the ways that human diseases are studied.