Ethyl pyruvate reduces mortality in an endotoxin-induced severe acute lung injury mouse model

<p>Abstract</p> <p>Background</p> <p>Ethyl pyruvate (EP) was recently identified as an experimental therapeutic agent in a wide variety of model systems for inflammation-mediated tissue and cellular injury.</p> <p>Objective</p> <p>To evaluate the effect of ethyl EP on improving the survival in mice with LPS-induced acute lung injury (ALI).</p> <p>Methods</p> <p>ALI was induced by administering lipopolysaccharide (LPS) intratracheally. The mice were treated intraperitoneally (i.p.) with 100, 50 and 10 mg/kg EP immediately before intratracheal instillation of LPS, and 100 mg/kg EP was administered 0, 12, 24 and 48 hours after induction of ALI. The mortality rate was recorded and analyzed by the Kaplan-Meier method. Serum tumor necrosis factor (TNF)-α, interleukin (IL) -6 and IL-1 β were measured in bronchial alveolar lavage fluid using an enzyme-linked immunosorbent assay. High-mobility group box 1 levels were measured by Western immunoblotting.</p> <p>Results</p> <p>Treatment with EP significantly inhibited the release of HMGB1, TNF-α, IL-6 and IL-1β into bronchoalveolar lavage (BAL) fluids of ALI mice, and reduced the permeability index of the injured lung. High EP doses reduced the mortality from ALI and the permeability index (100 mg/kg and 50 mg/kg EP versus control; P < 0.0001). Early administration of high-dose EP significantly increased survival rate (0, 12 and 24 h versus control; P < 0.0001, P < 0.0001 and P = 0.01 respectively by log-rank test). There was no survival advantage when EP was initiated at 48 h.</p> <p>Conclusion</p> <p>Ethyl pyruvate improves survival and reduces the lung permeability index in mice with LPS-induced ALI.</p

P-hydroxyphenylpyruvate, an intermediate of the Phe/Tyr catabolism, improves mitochondrial oxidative metabolism under stressing conditions and prolongs survival in rats subjected to profound hemorrhagic shock

The aim of this study was to test the effect of a small volume administration of p-hydroxyphenylpyruvate (pHPP) in a rat model of profound hemorrhagic shock and to assess a possible metabolic mechanism of action of the compound. The results obtained show that hemorrhaged rats treated with 2-4% of the estimated blood volume of pHPP survived significantly longer (p<0.001) than rats treated with vehicle. In vitro analysis on cultured EA.hy 926 cells demonstrated that pHPP improved cell growth rate and promoted cell survival under stressing conditions. Moreover, pHPP stimulated mitochondria-related respiration under ATP-synthesizing conditions and exhibited antioxidant activity toward mitochondria-generated reactive oxygen species. The compound effects reported in the in vitro and in vivo analyses were obtained in the same millimolar concentration range. These data disclose pHPP as an efficient energetic substrates-supplier to the mitochondrial respiratory chain as well as an antioxidant supporting the view that the compound warrants further evaluation as a therapeutic agent. © 2014 Cotoia et al

Introduction of an agent-based multi-scale modular architecture for dynamic knowledge representation of acute inflammation

<p>Abstract</p> <p>Background</p> <p>One of the greatest challenges facing biomedical research is the integration and sharing of vast amounts of information, not only for individual researchers, but also for the community at large. Agent Based Modeling (ABM) can provide a means of addressing this challenge via a unifying translational architecture for dynamic knowledge representation. This paper presents a series of linked ABMs representing multiple levels of biological organization. They are intended to translate the knowledge derived from in vitro models of acute inflammation to clinically relevant phenomenon such as multiple organ failure.</p> <p>Results and Discussion</p> <p>ABM development followed a sequence starting with relatively direct translation from in-vitro derived rules into a cell-as-agent level ABM, leading on to concatenated ABMs into multi-tissue models, eventually resulting in topologically linked aggregate multi-tissue ABMs modeling organ-organ crosstalk. As an underlying design principle organs were considered to be functionally composed of an epithelial surface, which determined organ integrity, and an endothelial/blood interface, representing the reaction surface for the initiation and propagation of inflammation. The development of the epithelial ABM derived from an in-vitro model of gut epithelial permeability is described. Next, the epithelial ABM was concatenated with the endothelial/inflammatory cell ABM to produce an organ model of the gut. This model was validated against in-vivo models of the inflammatory response of the gut to ischemia. Finally, the gut ABM was linked to a similarly constructed pulmonary ABM to simulate the gut-pulmonary axis in the pathogenesis of multiple organ failure. The behavior of this model was validated against in-vivo and clinical observations on the cross-talk between these two organ systems</p> <p>Conclusion</p> <p>A series of ABMs are presented extending from the level of intracellular mechanism to clinically observed behavior in the intensive care setting. The ABMs all utilize cell-level agents that encapsulate specific mechanistic knowledge extracted from in vitro experiments. The execution of the ABMs results in a dynamic representation of the multi-scale conceptual models derived from those experiments. These models represent a qualitative means of integrating basic scientific information on acute inflammation in a multi-scale, modular architecture as a means of conceptual model verification that can potentially be used to concatenate, communicate and advance community-wide knowledge.</p

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

Gut mucosal DAMPs in IBD: From mechanisms to therapeutic implications

Endogenous damage-associated molecular patterns (DAMPs) are released during tissue damage and have increasingly recognized roles in the etiology of many human diseases. The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), are immune-mediated conditions where high levels of DAMPs are observed. DAMPs such as calprotectin (S100A8/9) have an established clinical role as a biomarker in IBD. In this review, we use IBD as an archetypal common chronic inflammatory disease to focus on the conceptual and evidential importance of DAMPs in pathogenesis and why DAMPs represent an entirely new class of targets for clinical translation. </p

Optimal access regulation with downstream competition

We analyze the setting of access prices for a bottleneck facility where the facility owner also competes in the deregulated downstream market. We consider a continuum of market structures from Cournot to Bertrand. These market structures are fully characterized by a single parameter representing the intensity of competition. We first show how the efficient component pricing rule should be modified as the downstream competitive intensity changes. We then analyse the optimal access price where a regulator trades off production efficiency and pro-competitive effects to maximize total surplus