Non-steroidal anti-inflammatory agents (NSAIDs), such as acetyl salicylic acid and indometasin, have been used in the treatment of sepsis and septic shock, and an improve- ment in survival has been noted. Several researchers have also evaluated ibuprofen, and beneficial effects on patho- physiological changes have been observed . The first major study of ibuprofen in endotoxic shock was per- formed by Jacobs et al.. This study indicated that ibu- profen can limit the degree of hypotension and acidosis, and decrease the cardiac index in endotoxic shock. Fink et al.  reported that ibuprofen restored the normal hemo- dynamic pattern. However, Hulton et al.  saw no major metabolic effect in E. coli sepsis. Coran et al. showed that the administration of ibuprofen in septic shock in dogs did not reduce cytokine levels. Herbertson et al. showed that ibuprofen administration in endotoxic shock in pigs could prevent the early hemodynamic changes fol- lowing entotoxemia, but not the later changes. Bernard et al.  reported that, in patients with sepsis, treatment with ibuprofen reduced levels of prostacylin and throm- boxane and decreased fever, tachycardia, oxygen con- sumption, and lactic acidosis, but did not prevent the development of shock or acute respiratory distress syn- drome, and did not improve survival.
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endotoxic shock, it was found that the lethal dose of LPS for IL10T mice was 20-fold lower than that for wild type (wt) mice suggesting that endogenous IL-10 determines the amount of LPS which can be tolerated without death. The high mortality rate of IL10T mice challenged with modest doses of LPS was correlated to the uncontrolled production of TNF as
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Abstract: Objective: This study aims to explore the effects of BML-111 and MAPK signaling pathway on the expres- sion of AQP1 in rat lung tissue of acute lung injury caused by endotoxic shock. Methods: Acute lung injury caused by LPS mouse model was established. They were divided into normal group, ALI model group, BML group, SB group and SP group. Wet and dry weight of the right lung was detected, number of neutrophils and pulmonary permeability index were determined. Pathological morphology of lung tissues was determined by HE staining. The levels of TNF-α, IL-1β and IL-6 were determined by ELISA. The levels of AQP1, p38 and JNK were determined by western-blotting method. Results: There was pulmonary interstitial edema and thickening alveolar wall in ALI model group, the ra- tion of W/D, PPI, the number of neutrophils and the levels of TNF-α, IL-1β, IL-6, p38 MAPK and JNK phosphorylation increased, while the levels of AQP1 decreased when compared with normal group (P<0.01). However, W/D, PPI, the levels of TNF-α, IL-1β, IL-6 and the phosphorylation levels of p38 MAPK and JNK in BML group, SB group and SP group were significantly lower than that of model group (P<0.01), while the levels of AQP1 increased in BML group, SB group and SP group (P<0.01). Conclusions: BML-111, P38 MAPK inhibitor and JNK inhibitor could significantly inhibit the lung injury in ALI rats induced by LPS and increased the levels of AQP1, which may be through the inacti- vation of MAPK p38 and JNK signaling pathway.
Protection from endotoxic shock by isoflurane anesthesia correlates with attenuation of the inflammatory process. The reduced mortality of anesthetized mice after LPS injection may be due to attenuation of the systemic inflammatory response induced by LPS. To test this idea, mice were injected with LPS and exposed to isoflurane for 1 h immediately (simultaneous group) or 30 min after the LPS injection (post-LPS injection group). These two groups were compared with nonanesthe- tized mice injected with LPS (control). Plasma samples were collected 1.5 h after LPS injection for each group. A decrease in TNF- ␣ plasma levels was observed for the simultaneous group in comparison with levels for the other two groups (Fig. 1B). IL-6 and IL-10 levels were also reduced in the simulta- neous and post-LPS injection groups compared to levels for the control group (Fig. 1B). To further characterize these findings, the effect of isoflurane pretreatment was investigated. Compared to levels in the LPS control group, TNF- ␣ plasma levels 1.5 h after LPS injection were reduced in both the pre- treatment/recovery and the pretreatment group. However, TNF- ␣ levels for the two pretreatment groups were still sig- nificantly greater than the level for the simultaneous group (Fig. 1C). In contrast, IL-6 plasma levels were reduced only with the pretreatment and simultaneous groups, compared to levels for the control and pretreatment/recovery groups (Fig. 1C). Finally, IL-10 plasma levels in both pretreatment groups were greater than levels in the simultaneous and control groups (Fig. 1C). These data suggest that the suppressive effect of isoflurane on LPS-induced cytokine production increases survival in anesthetized animals. We also evaluated the effect of isoflurane anesthesia duration on the inflammatory re- sponse induced by LPS. Mice were injected with LPS and then administered continuous anesthesia for 0, 10, 30, or 60 min. Cytokine plasma levels were measured 1.5 h after injection. Decreasing levels of TNF- ␣ and IL-6 were observed with in- creasing duration of anesthesia, whereas IL-10 levels de- creased only with the 60-min anesthesia group (Fig. 2). There- fore, the timing and duration of isoflurane administration are important in modulating the LPS-induced inflammatory re- sponse.
To test the hypothesis that ablation of transient receptor potential vanilloid type 1 (TRPV1) channels leads to exacerbated in- flammatory responses and organ damage during endotoxic shock, lipopolysaccharide (LPS; 5 million endotoxin units/kg of body weight) was injected intraperitoneally (i.p.) into wild-type (WT) and TRPV1-null mutant (TRPV1 ⴚ/ⴚ ) mice. Mean arterial pres- sure and heart rate, determined by radiotelemetry, were severely depressed after LPS injection into WT and TRPV1 ⴚ/ⴚ mice, with no distinction between the two strains. At 24 h after LPS injection, renal glomerular hypercellularity and hepatocellular injury were observed in both strains, accompanying further elevated serum levels of creatinine and alanine aminotransferase in TRPV1 ⴚ/ⴚ mice compared to those in WT mice. At 6 or 24 h after LPS injection, neutrophil recruitment into kidneys and livers, serum cytokine (tumor necrosis factor alpha [TNF-␣], interleukin 1␤ [IL-1␤], IL-6) and renal chemokine (KC, macrophage in- flammatory protein 2 [MIP-2]) levels, and renal VCAM-1 and ICAM-1 expression were greater in TRPV1 ⴚ/ⴚ mice than WT mice. In addition, increased plasma calcitonin gene-related peptide (CGRP) levels observed in WT mice 6 h after LPS injection were absent in TRPV1 ⴚ/ⴚ mice. Thus, TRPV1 ablation aggravates inflammatory responses, including neutrophil infiltration, proin- flammatory cytokine production, and adhesion molecule expression, leading to intensified organ damage during endotoxic shock in the absence of worsened circulatory failure. The data indicate that TRPV1 activation may attenuate endotoxin-induced organ damage, possibly via its anti-inflammatory action rather than alteration of hemodynamics.
Evaluation of the ability of JM1226 to reverse the hypotension in LPS- treated rats. Using the well established model of endotoxic shock in male Wistar rats (see Chapter 3), two experiments were conducted to examine the ability of JM1226 to reverse the ensuing hypotension following LPS treatment. Blood pressure measurements were made in thirteen conscious rats (250 - 340g) at various times after a single injection of LPS (4mg/Kg; i.p.), followed later (at t= 20hrs) by a second injection of either (a) sterile saline (grp. 1) or (b) a sterile solution (lOOmg/Kg) of JM1226 (grp. 2). In the first experiment, blood pressures were measured at t= 0, 20 and 24hrs. In the second experiment recordings were made at t= 0, 20, 24, 29 and 32hrs. All blood pressure measurements were made using the tail cuff method (see Chapter 3, Section 3.5.1) and animals were familiarised to the procedure by a ‘training’ regimen (daily, for 1 or 4 weeks) before commencing an experiment so as to avoid undue stress. Recordings of systolic (S.b.p), mean (M.b.p.) and diastolic (Db.p.) arterial pressures were made at the following times relative to the time (t= Ohr) at which animals were injected with LPS: t= 0, 20, 24, 29 & 32hrs. Experiments 1& 2 followed exactly the same protocol and because blood pressure readings were made in the morning and afternoon a study was carried out on a group of rats (n= 8)to determine if this influenced the results. Blood pressure (b.p.) readings made in the morning were not significantly different from those made in the afternoon (results not shown).
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to the carbon dioxide partial pressure targeted to the physiological range) and an inspired fraction of oxygen of 60%. Arterial blood was sampled for gas analysis to adjust the ventilator setting in case of respiratory acido- sis prior to endotoxic shock induction. The right internal jugular vein and femoral artery were surgically isolated, and a central vein catheter was placed to infuse fluids and drugs. A dedicated arterial thermodilution catheter (4 Fr, 8 cm Pulsiocath PV2014L16; Pulsion Medical Systems, Munich, Germany) was inserted to acquire the haemo- dynamic measurements . Lactate Ringer’s solution (4 mL kg −1 h −1 ) was infused in the central vein catheter,
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DNA single strand breakage and activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) contribute to peroxynitrite-induced cellular injury. We investigated the role of PARS activation in the pathogenesis of endothelial dysfunction. In human umbilical vein endothelial cells (HUVEC), DNA strand breakage (alkaline unwinding assay), PARS activation (incorporation or radiolabeled NAD+ into proteins), mitochondrial respiration [conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to formazan] and apoptotic index (cytoplasmatic release of histones) were measured. Endotoxin shock was induced in rats by bacterial lipopolysaccharide. Vascular reactivity of thoracic aortic rings were measured in organ chambers. In HUVEC, peroxynitrite caused a dose-dependent suppression of mitochondrial respiration, induced DNA strand breakage and caused an activation of PARS. Pharmacological inhibition of PARS reduced the acute and delayed suppression of mitochondrial respiration when cells were exposed to intermediate, but not high doses of peroxynitrite. Similarly, protection against the intermediate, but not high doses of peroxynitrite was seen in fibroblasts from the PARS-/- mice, when compared to wild-type controls. These data suggest that PARS plays a role in peroxynitrite-induced cytotoxicity, but at very high levels of oxidant exposure, PARS-independent cytotoxic mechanisms become predominant. Peroxynitrite-induced apoptosis was not affected by PARS inhibition. Vascular rings exposed to peroxynitrite and rings taken from rats subjected to endotoxic shock exhibited reduced endothelium-dependent relaxant responses in response to acetylcholine. The development of this endothelial dysfunction […]
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cardiac output and vascular tone , and on improve- ment of regional microcirculation without fluid overload . However, with the potentially beneficial sodium cation, the presence of non-metabolized chloride anion may have detrimental effects. Supraphysiological concen- trations of chloride, which induce hyperchloremia and metabolic acidosis, may cause renal vasoconstriction and decreased glomerular filtration rate . Moreover, in a recent study, a chloride-restrictive strategy in intensive care units was associated with a significant decrease in the incidence of acute kidney injury and in the use of renal replacement therapy . Hence, in an attempt to avoid the detrimental effects of non-metabolized anion, the use of metabolized anions such as lactate may be required. The use of lactate is an interesting alternative because this anion is well-metabolized  even in poor hemodynamic conditions . Some positive clinical experience in using sodium lactate is available. In cardiac surgery, exogenous lactate has been shown to improve cardiac index and has been shown to be safe and well-tolerated . Lactate may serve as a resuscitation fluid-based energetic sub- strate providing a high-octane fuel  to improve heart performance [19,21], and simultaneously to normalize fluid balance [14,21]. There are no data available on the administration of hypertonic sodium lactate in sepsis or septic shock. Based on the potential interest in sodium- lactate as an energy substrate and resuscitative fluid, we investigated the effects of hypertonic sodium lactate on fluid balance, hemodynamic and microcirculation in a porcine model of endotoxic shock.
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In the setting of sepsis and septic shock, these effects can eventually lead to death. It would be expected that an increase in antioxidant level or the enhancement of antioxi- dant enzyme activity would decrease oxidative stress, leading to decreased inflammatory response and improved outcome. However, a recent publication by Meissner et al indicated that in a murine endotoxic shock model, a deficiency of SOD1 provided protection against the effects of lipopolysaccharide (LPS). 6 In addition, de Vos et al found that overexpression of
Another explanation for the prevention of fluid overload with sodium lactate could be an improvement in endothe- lial barrier function, as recently described in pediatric severe Dengue infection . Although the pathogenesis of endotoxic shock is different from septic shock, endo- thelial cell dysfunction is common in both situations. In fact, porcine endotoxic shock is characterized by a severe vascular systemic capillary leak syndrome, and histologic findings supported the development of a respiratory distress syndrome with marked pulmonary leukocyte sequestration and interstitial edema . In our model, sodium lactate infusion appeared to reduce capillary leak- age, particularly in the lung. In fact, sodium lactate infu- sion preserved the PaO 2 /FiO 2 ratio compared to the
In contrast to shocked controls, rats pretreated with imidazole, a thromboxane synthetase inhibitor, or essential fatty acid-deficient rats, which are deficient in arachidonate and its metabolites, did not exhibit significant elevations in plasma levels of thromboxane B 2 . Imidazole did not however inhibit endotoxin-induced elevations in plasma prostaglandin E. Essential fatty acid deficiency significantly reduced mortality to lethal endotoxic shock. This refractoriness could be duplicated in normal rats pretreated with the fatty acid cyclo-
We previously observed that sodium lactate infu- sion enhanced fluid balance in pig endotoxic shock [25, 26]. This beneficial effect of sodium lactate could not be totally explained neither by its hyperosmolar or alka- lizing effects  nor by its energy load or its effect on the chloride balance . Finally, two additional mecha- nisms have been hypothesized: first, lactate infusion is better metabolized in poor hemodynamic conditions than glucose, and second, lactate could decrease proin- flammatory response and/or improve endothelial barrier function. Interestingly, it is well known that proinflam- matory response and endothelial dysfunction exacerbate the endotoxin-induced DIC [27, 28]. So, in order to bet- ter understand the beneficial effect of sodium lactate on fluid balance, we conducted an ancillary work focused on DIC and renal histology.
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Endotoxemia is a potentially devastating complication of several diseases of cattle e.g. enteric disease, septicemia, metritis, mastitis and pneumonia . Endotoxemia is a life threatening inflammatory condition which can lead to shock, multiple organ failure, suppression of immune system and wound healing processes . After gaining access to the circulation, endotoxin causes a variety of adverse effects including cardiovascular compromise, lactic acidiosis, leukopenia, glucose dyshomeostasis, hemostatic alteration, gastrointestinal,respiratory and renal disturbances. The traditional treatment for en- dotoxemic animals attempts to support cardiac and pul- monary function, eliminate causative microbes and modulate the production of endogenous mediators. While hypertonic saline is cheap, easily available and has been reported to bring immediate beneficial effects which are transient , flunixin meglumine inhibits the release of endogenous inflammatory mediators. The present investigation was carried out to elucidate the effects of flunixin meglumine- a NSAID alone and in combination with hypertonic saline solution on hemo- dynamics of endotoxemic buffalo calves.
cellulose sodium solution, which served as a vehicle for analysis. Male C57BL/6 mice weighing 18–22 g were orally pretreated with the n-butanol extract solution (5 g/kg/day) for 7 days before receiving an injection of LPS (20 or 10 mg/kg) into the caudal vein. Control animals received a similar volume (200 µ L) of the vehicle. For septic survival analysis (LPS at 20 mg/kg), mortality was recorded every 12 hours for 7 days. For septic shock response evaluation (LPS at 10 mg/kg), mice were euthanized under ether anesthesia 4 hours after LPS injection, and then their lung tissues were embedded in paraffin for histopathological examination (n = 10 in each group).
Methods: This prospective case–control study in the medical–surgical intensive care unit of a university hospital included consecutive adults patients with septic shock and suspected gram-negative bacteria infection with elevated plasma endotoxin activity (EAA > 0.6 EU/ml) and acute kidney injury requiring continuous renal replacement therapy (CRRT). At onset of septic shock, half underwent CRRT plus hemoperfusion with polymyxin B for two hours a day dur- ing two consecutive days (hemoperfusion group) and half received only CRRT (control group). We measured clinical, physiological, and biological parameters (EAA, C-reactive protein, procalcitonin, and cytokines) daily during the first 5 days.
Macrophages are induced by LPS to release a number of products that determine the host response during gram negative sepsis. To examine the role of one such substance, tumor necrosis factor (TNF), in mediating LPS-induced injury, we employed a rabbit model of endotoxic shock to (a) determine the kinetics and extent of release of TNF into plasma after injection of LPS, and (b) to evaluate the protective effect of in vivo neutralization of LPS- induced TNF by prior infusion of anti-TNF antibody. TNF was maximally induced 45-100 min after injection of 10 micrograms i.v. parent Salmonella minnesota Re595 LPS or 250 micrograms Re595 LPS-HDL complexes. Maximal induction of TNF by LPS was
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Septic or endotoxic shock is an acute circulatory failure occurring in the presence of severe infection and represents an imbalance between the body’s oxygen demands and supply. It is principally of the dis- tributive type, although cardiogenic and hypovolemic components may also be involved . Endotoxin is an integral component of the outer membrane of gram-negative bacteria and the effects of exposure of host cells to it include the uncontrolled release of cytokines and eicosanoids, kinins and other short, me- dium and long-term reactants that upset the balance between proinflammatory and anti-inflammatory pathways, causing hypotension, disseminated intravascular coagulation, abortion and death . Endo- toxemia is a life threatening inflammatory condition, which can lead to shock, multiple organ failure, sup- pression of immune system and wound-healing processes .
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All sick children were initially evaluated in the emergency room of the hospital and initial stabilization of the patient including airway, breathing followed by fluid resuscitation was carried out.Children presenting with acute watery diarrhea were admitted in the PICU only if they require some intensive care in the form of ventilation, inotrope support or dialysis.All other cases of shock were admitted in PICU.
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The posterior distributions obtained from the simulation via Metropolis-Hastings algorithm exhibit good properties in terms of convergence of the parameters. Most of the posterior distributions have smooth densities and differ from their prior distributions. The state space form of rational expectations solution of the model are used to determine unobservable state variables of the model and assess the contribution of structural shocks. The findings indicate that the estimated output gap has been negative during the Great Recession and oil price declines. It has also been shown that most of the variation in output gap has been due to the consumption and export income shocks. Inflation rate gap has been stable at its steady for the most period with infrequent outbursts in 2008 and 2015. The model allowed us to determine the fundamental sources of two upward spikes in the inflation rate gap, which in the first case was due to pure inflationary shocks, whereas in the second case it was due to consumption, risk premium and export income shocks. It has also been found that productivity shocks account for almost half of the forecast error variance decomposition in observed GDP growth whereas pure inflationary shocks account for 80% of the variance decomposition in inflation rate. The most interesting finding that justifies the effort of including risk premium into the model is that almost 60% of variation in nominal exchange rate comes from risk premium shocks. In addition, the model is used for analyzing the responses of endogenous variables to monetary policy and other relevant shocks. A contractionary monetary policy leads to a decrease in output gap, exchange rate appreciation and a negligible impact on inflation rate. Hence, it is deduced that the monetary policy is rather ineffective in lowering inflation by raising interest rates. Both productivity and export income shocks lead to an expansion of output gap and a decrease in inflation rate, but the effect of export income shock on the economy is more persistent. The effect of risk premium shock is similar to the events that have been observed in 2015, when there was a speculative attack on the currency. The impulse responses of the model shows us that the exchange rate depreciates significantly whereas output decreases and inflation rate rises. The consumption of households decline in response to a higher interest rate and lower purchasing power of domestic currency. Hence, the model precisely predicts the direction of responses of endogenous variables during the speculative attack on the domestic currency in 2015. Overall, the model gives sound results on the fundamental sources of fluctuations in the economy and the transmission mechanisms of structural shocks.
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