Animal models of sepsis and sepsis-induced kidney injury

Department of Nephrology and Endocrinology, University of Tokyo, Tokyo, Japan.
The Journal of clinical investigation (Impact Factor: 13.22). 10/2009; 119(10):2868-78. DOI: 10.1172/JCI39421
Source: PubMed


Sepsis is characterized by a severe inflammatory response to infection, and its complications, including acute kidney injury, can be fatal. Animal models that correctly mimic human disease are extremely valuable because they hasten the development of clinically useful therapeutics. Too often, however, animal models do not properly mimic human disease. In this Review, we outline a bedside-to-bench-to-bedside approach that has resulted in improved animal models for the study of sepsis - a complex disease for which preventive and therapeutic strategies are unfortunately lacking. We also highlight a few of the promising avenues for therapeutic advances and biomarkers for sepsis and sepsis-induced acute kidney injury. Finally, we review how the study of drug targets and biomarkers are affected by and in turn have influenced these evolving animal models.

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    • "We could not determine why the patients whose blood isolates possessed the hypermucoviscosity phenotype significantly suffered septic shock. Lipopolysaccharide (LPS) or endotoxin has been shown to be a virulence factor for gram-negative bacteria, which is a potent inducer of host inflammatory cascade via innate receptor pathways [23] [24]. Actually, endotoxin removal device has been widely used in Japan to treat patients with sepsis [25]. "
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    ABSTRACT: Ninety-four episodes of Klebsiella pneumoniae bloodstream infection were identified at a university hospital in Japan. After excluding extended-spectrum beta lactamase-producing strains, 83 blood isolates from these patients were assayed in terms of their bacterial phenotypes such as the mucoid and hypermucoviscosity phenotypes. Bacterial phenotypes were correlated with the patients' clinical manifestations. The hypermucoviscosity phenotype was significantly associated with septic shock at the onset of infections (odds ratio, 15.92; 95% confidence interval, 1.27-468.12), but was not associated with liver abscess formation. Mortality was determined by the presence of septic shock. RmpA gene was associated with the induction of the hypermucoviscosity phenotype. These results reveal unique roles of bacterial phenotypes on the patient's clinical condition in K. pneumoniae bacteremia. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Infection and Chemotherapy 04/2015; 21(7). DOI:10.1016/j.jiac.2015.04.004 · 1.49 Impact Factor
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    • "Currently, several mouse models were established to study sepsis with the hope of better understanding the pathophysiological mechanisms so that new therapies could be developed. Sepsis models can be divided into two categories as follows: the lipopolysaccharide model by injecting an exogenous toxin and the CLP model by altering the endogenous protective barrier [30]. Our present study chose the most widely used CLP model to induce sepsis, knowing that CLP-induced sepsis in murine animals exhibits a cytokine profile similar to that in human sepsis. "
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    ABSTRACT: Salidroside (SDS) is the main effective component of Rhodiola rosea L with a variety of pharmacologic properties. The objective of this study was to investigate the efficacy of SDS in the treatment of experimental sepsis in mice and explore the possible underlying action mechanisms. Sepsis was induced in C57BL/6 male mice via cecal ligation and puncture (CLP). The animals were divided into three groups as follows: sham, CLP, and CLP plus SDS. SDS (50 mg/kg) was injected intraperitoneally 1 h after operation. Postoperative survival of the mice, bacterial clearance in blood and peritoneal lavage fluid, cytokine secretion in blood, and histology of lung were evaluated. In addition, apoptosis of immune cells in the spleen and thymus were examined, respectively. SDS administration prolonged the survival of the septic mice, inhibited the proinflammatory responses, and enhanced bacterial clearance. It also alleviated the pathologic changes in the lung and inhibited the apoptosis of immune cells in the spleen and thymus after CLP challenge. SDS exerts a protective effect in CLP-induced sepsis by attenuating the proinflammatory responses, enhancing bacterial clearance, and preserving adaptive immunity. SDS may be a promising therapeutic strategy for the treatment of sepsis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Journal of Surgical Research 01/2015; 195(1). DOI:10.1016/j.jss.2015.01.021 · 1.94 Impact Factor
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    • "The pathogenesis of sepsis depends predominantly on lipopolysaccharide (LPS), which is a membrane component of gram negative bacteria responsible for the endotoxic activity [4]. Therefore, administration of LPS to animals has been extensively used to mimic sepsis [5]. "
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    ABSTRACT: Background The ubiquitin-proteasome pathway (UPP) is a major protein degradation pathway that is activated during sepsis and has been proposed as a therapeutic target for preventing skeletal muscle loss due to cachexia. Although several studies have investigated the modulation of proteasome activity in response to LPS administration, none have characterized the overall UPP response to LPS administration in the fate of proteasome inhibition. Methods Here, we determined the modulation pattern of the main key components of the UPP in the gastrocnemius (GAS) of mice during the acute phase of lipopolysaccharide (LPS)-mediated endotoxemia (7.5 mg/kg – 8 h) by measuring all three β1, β2 and β5 activites of the 20S and 26S proteasomes, the levels of steady state polyubiquitinated proteins, mRNA levels of muscle ligases, as well as signaling pathways regulating the UPP. Another goal was to assess the effects of administration of a specific proteasome inhibitor (epoxomicin, 0.5 mg/kg) on UPP response to sepsis. Results The acute phase of LPS-induced endotoxemia lowered GAS/body weight ratio and increased MuRF1 and MAFbx mRNA concomitantly to an activation of the pathways known to regulate their expression. Unexpectedly, we observed a decrease in all 20S and 26S proteasome activities measured in GAS, which might be related to oxidative stress, as oxidized proteins (carbonyl levels) increase with LPS. While significantly inhibiting 20S and 26S proteasome β5 activities in heart and liver, epoxomicin did not lower proteasome activity in GAS. However, the increase in mRNA expression of the muscle ligases MuRF1 and MAFbx were partially rescued without affecting the other investigated signaling pathways. LPS also strongly activated autophagy, which could explain the observed GAS atrophy with LPS-induced reduction of proteasome activity. Conclusions Our results highlight an opposite regulation of UPP in the early hours of LPS-induced muscle atrophy by showing reduced proteasome activities and increased mRNA expression of muscle specific ligases. Furthermore, our data do not support any preventive effect of epoxomicin in muscle atrophy due to acute cachexia since proteasome activities are not further repressed.
    BMC Musculoskeletal Disorders 05/2014; 15(1):166. DOI:10.1186/1471-2474-15-166 · 1.72 Impact Factor
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