A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R 2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.human disease | translational medicine | inflammation | immune response | injury M urine 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 respo...

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes.

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In injured patients at risk for hemorrhagic shock, the prehospital administration of thawed plasma was safe and resulted in lower 30-day mortality and a lower median prothrombin-time ratio than standard-care resuscitation. (Funded by the U.S. Army Medical Research and Materiel Command; PAMPer ClinicalTrials.gov number, NCT01818427 .).

C. difficile colitis is a significant and increasing cause of death. Surgical treatment of C. difficile colitis has a high death rate once the fulminant expression of the disease is present.

In this multicenter study, 38.5% of adults with blunt splenic injury went directly to laparotomy. Ultimately, 54.8% of patients were successfully managed nonoperatively; the failure rate of planned observation was 10.8%, with 60.9% of failures occurring in the first 24 hours. Successful nonoperative management was associated with higher blood pressure and hematocrit, and less severe injury based on ISS, Glasgow Coma Scale, grade of splenic injury, and quantity of hemoperitoneum.

SummaryResuscitation from hemorrhagic shock induces profound changes in the physiologic processes of many tissues and activates inflammatory cascades that include the activation of stress transcriptional factors and upregulation of cytokine synthesis. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that the inducible nitric oxide synthase (iNOS) is expressed during hemorrhagic shock. We postulated that nitric oxide production from iNOS would participate in proinflammatory signaling. Using the iNOS inhibitor N 6 -(iminoethyl)-l -lysine or iNOS knockout mice we found that the activation of the transcriptional factors nuclear factor B and signal transducer and activator of transcription 3 and increases in IL-6 and G-CSF messenger RNA levels in the lungs and livers measured 4 h after resuscitation from hemorrhagic shock were iNOS dependent. Furthermore, iNOS inhibition resulted in a marked reduction of lung and liver injury produced by hemorrhagic shock. Thus, induced nitric oxide is essential for the upregulation of the inflammatory response in resuscitated hemorrhagic shock and participates in end organ damage under these conditions. H emorrhagic shock initiates an inflammatory response characterized by the upregulation of cytokine expression (1) and accumulation of neutrophils (2) in a variety of tissues. These changes are prominent in the lungs and liver and are likely to contribute to end organ damage and resultant dysfunction after shock. The mechanisms by which hemorrhage triggers this inflammatory response remain poorly understood. Heightened adrenergic activity (3) and systemic release of proinflammatory agents from the gut (4, 5) have been hypothesized to contribute to acute lung injury after hemorrhage. In addition, reactive radicals are produced after ischemia/reperfusion and resuscitation from hemorrhagic shock, and have been implicated in a number of signal transduction pathways (6).Among the important radicals produced during hemorrhagic shock is the bioregulatory molecule nitric oxide (NO) 1 generated catalytically by three enzymes collectively termed NO synthases. We (7) and others (8) have shown that the inflammatory or inducible NO synthase (iNOS or NOS2) is upregulated in both the lungs and liver during shock. Therefore, this isoform may be capable of catalyzing the sustained production of NO after the tissue reperfusion associated with fluid resuscitation. NO can have both direct effects on cell signaling as well as indirect actions mediated by the reaction products formed when NO interacts with other molecules such as oxygen or superoxide (9). We hypothesized that enhanced NO production resulting from iNOS expression would contribute to proinflammatory signaling in hemorrhagic shock. Hemorrhagic shock experiments were therefore carried out in rats treated with the iNOS-selective inhibitor N 6 -(iminoethyl)-l -lysine (L-NIL; reference 10) and mice genetically deficient in iNOS. We report here that iNOS inhibition or deficiency prevents t...

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