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  • Other specific concerns raised in preclinical


    Other specific concerns raised in preclinical models of sepsis include the use of animals that are young, without comorbidities, of the same gender, and the absence of supportive therapies such as Paclitaxel (Taxol) or fluid [44]. This heterogeneity has resulted in variable physiological responses and outcomes that could, at least partially, explain the conflicting results and the failure of novel therapies to translate to the clinical setting.
    Pathophysiology of SIC
    Mitochondrial dysfunction in sepsis
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    Introduction Systemic inflammation in the critically ill patient is often accompanied by an impairment of the microcirculation [1] that contributes to the development of organ dysfunction [2]. The exposure of the microvascular endothelium to inflammatory mediators can result in an activated pro-coagulant state with microthrombi formation as well as a severe impairment of the endothelial barrier [3]. This leads to capillary leakage and interstitial oedema resulting in decreased tissue oxygenation facilitating the onset of organ dysfunction [4]. Thus, the development of preventive or therapeutic strategies stabilizing endothelial barriers may improve the outcome in patients suffering from conditions associated with severe systemic inflammation, such as sepsis. Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator circulating mostly in the blood, influencing cellular migration, proliferation and survival via its G protein-coupled receptors S1P1–5 [5]. S1P potently promotes barrier function in vitro [[6], [7], [8]] and is essential for maintenance of endothelial barriers in vivo [9,10]. Our group and others have shown that serum S1P levels are lower in septic patients and correlate negatively with the severity of disease. This indicates a role of S1P in the pathophysiology of endothelial dysfunction [[11], [12], [13]]. FTY720 – a clinically approved S1P analogue for treatment of multiple sclerosis – enhances the endothelial barrier in cultured pulmonary or brain endothelial cells [[14], [15], [16]] and reduces barrier-permeabilizing effects of VEGF [17] and TNF–α [15,18]. In a previous study by our group, administration of FTY720 improved cardiac dysfunction and was associated with elevated S1P serum levels in murine sepsis models [11]. Others have further shown that FTY720 reduces fluid extravasation in a rat model of sepsis [19] and lung microvascular permeability in LPS-challenged mice [20]. Additionally, Imeri et al. [15,18] reported a protective effect of FTY720 and S1P in the human endothelial cell line EA.hy 926 and in mouse and human microcapillary brain endothelial cells. This protection was suggested to involve an upregulation of the adherens junction molecule PECAM-1 (CD31) [15]. Targeting the S1P pathway might consequently be an interesting therapeutic approach to stabilize microvascular endothelial barriers. The effects of FTY720 on the glomerular endothelium in an inflammatory state have not yet been investigated. The heterotrimeric AMP-dependent protein kinase (AMPK) is widely expressed in the endothelium [21] and previous in vivo and in vitro studies have shown that AMPK exerts anti-inflammatory and protective effects on the endothelial barrier under inflammatory conditions [[22], [23], [24]]. Of note, S1P is one of the agonists that can activate AMPK and targets further downstream in cultured bovine aortic cells [25] as well as human umbilical vein endothelial cells and baby hamster kidney cells [26,27] indicating that AMPK could be one of the mediators promoting the barrier-enhancing effects of S1P. However, the interaction of S1P and AMPK has not yet been investigated in the microvascular endothelium and the functional relevance of their interrelationship for the endothelial barrier remains unclear. Although barrier dysfunction mainly affects the microvasculature, cells derived from the macrovasculature are often used to study endothelial barrier breakdown. It has previously been shown that endothelial cells have heterogeneous phenotypes regarding their permeability depending on the vascular branch from which they originate. This is, at least in part, influenced by different patterns of adhesion molecule and tight junction expression [28]. Tissue of origin also plays an important role, e.g. glomerular endothelium is highly fenestrated whereas both brain and dermal microvascular endothelial cells belong to the continuous endothelium. Still, brain and dermal microvascular endothelial cells differ regarding their caveolin as well as tight junction protein expression [28]. However, this fact is often neglected and might explain why in vitro observations often deviate from in vivo findings [29].