Article

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

ABSTRACT

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.

Download full-text

Full-text

Available from: Peter S T Yuen
    • "Diminished efficacy of endogenous TxA 2 and direct depolarisation secondary to dysfunction of the RhoA/ROK pathway may contribute to systemic hypotension in septic shock and dysregulation of regional blood flow[18,20]. To address this gap in knowledge, we used a murine caecal ligation and puncture (CLP) model of sepsis that included an intensive care treatment regimen that simulated the clinical experience of a septic patient[21,22]. CLP is a well-described, reproducible model of sepsis incorporating polymicrobial infection and tissue necrosis[23,24]. As an animal model, it replicates many of the physiological, haemodynamic and metabolic sequelae of sepsis25262728. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sepsis is characterised by diminished vasopressor responsiveness. Vasoconstriction depends upon a balance: Ca(2+)-dependent myosin light-chain kinase promotes and Ca(2+)-independent myosin light-chain phosphatase (MLCP) opposes vascular smooth muscle contraction. The enzyme Rho kinase (ROK) inhibits MLCP, favouring vasoconstriction. We tested the hypothesis that ROK-dependent MLCP inhibition was attenuated in late sepsis and associated with reduced contractile responses to certain vasopressor agents. This is a prospective, controlled animal study. Sixteen-week-old C57/BL6 mice received laparotomy or laparotomy with caecal ligation and puncture (CLP). Antibiotics, fluids and analgesia were provided before sacrifice on day 5. Vasoconstriction of the femoral arteries to a range of stimuli was assessed using myography: (i) depolarisation with 87 mM K(+) assessed voltage-gated Ca(2+) channels (L-type, Cav1.2 Ca(2+) channels (LTCC)), (ii) thromboxane A2 receptor activation assessed the activation state of the LTCC and ROK/MLCP axis, (iii) direct PKC activation (phorbol-dibutyrate (PDBu), 5 μM) assessed the PKC/CPI-17 axis independent of Ca(2+) entry and (iv) α1-adrenoceptor stimulation with phenylephrine (10(-8) to 10(-4) M) and noradrenaline (10(-8) to 10(-4) M) assessed the sum of these pathways plus the role of the sarcoplasmic reticulum (SR). ROK-dependent MLCP activity was indexed by Western blot analysis of P[Thr855]MYPT. Parametric and non-parametric data were analysed using unpaired Student's t-tests and Mann-Whitney tests, respectively. ROK-dependent inhibition of MLCP activity was attenuated in both unstimulated (n = 6 to 7) and stimulated (n = 8 to 12) vessels from mice that had undergone CLP (p < 0.05). Vessels from CLP mice demonstrated reduced vasoconstriction to K(+), thromboxane A2 receptor activation and PKC activation (n = 8 to 13; p < 0.05). α1-adrenergic responses were unchanged (n = 7 to 12). In a murine model of sepsis, ROK-dependent inhibition of MLCP activity in vessels from septic mice was reduced. Responses to K(+) depolarisation, thromboxane A2 receptor activation and PKC activation were diminished in vitro whilst α1-adrenergic responses remained intact. Inhibiting MLCP may present a novel therapeutic target to manage sepsis-induced vascular dysfunction.
    No preview · Article · Dec 2015
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Apr 2015 · Journal of Infection and Chemotherapy
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jan 2015 · Journal of Surgical Research
Show more