Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule that selectively inhibits Toll-like receptor 4-mediated signaling, inhibits various kinds of inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-10, macrophage inhibitory protein (MIP)-2 and prostaglandin E2 from lipopolysaccharide (LPS)-stimulated macrophages. The effects of TAK-242 were evaluated in a mouse model of endotoxin shock. Intravenous administration of TAK-242 to mice 1 h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-alpha, IL-1beta, IL-6, IL-10, MIP-2, and NO metabolites. TAK-242 protected mice from LPS-induced lethality in a similar dose-dependent manner, and rescued 100% of mice at a dose of 1 mg/kg. Interestingly, TAK-242 worked quickly, and showed beneficial effects even when administered after LPS challenge. Even though increases in serum levels of IL-6 and hypothermia were already evident 2 h after LPS challenge, TAK-242 administration inhibited further increase in IL-6 levels and decrease in body temperature. LPS-induced increases in serum levels of organ dysfunction markers, such as alanine aminotransferase, total bilirubin, and blood urea nitrogen, were also significantly suppressed by post-treatment as well as pre-treatment. Furthermore, administration of 3 mg/kg TAK-242 significantly increased survival of mice, even when given 4 h after LPS challenge. These results suggest that TAK-242 protects mice against LPS-induced lethality by inhibiting production of multiple cytokines and NO. TAK-242 has a quick onset of action and provides significant benefits by post-treatment, suggesting that it may be a promising drug candidate for the treatment of sepsis.
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PMID:Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. 1763

We tested the hypothesis that laminarin (LAM), a beta (1-3) polysaccharide extracted from brown algae, can modulate the response to a systemic inflammation. Male Wistar rats (n=7 per group) were fed a standard diet (control) or a diet supplemented with LAM for 25 days (5% during 4 days followed by 10% during 21 days). Thereafter, Escherichia coli lipopolysaccharides (LPS; 10 mg/kg i.p.) were injected and the animals were sacrificed 24 h after LPS challenge. The hypothermia, hyperglycemia and hypertriglyceridemia occurring early after LPS administration were less pronounced in LAM-treated rats than in controls. The increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities - reflecting hepatic alterations - was lessened after LPS injection in LAM-treated rats compared to control rats. LAM treatment decreased serum monocytes number, nitrite (NO2) and tumor necrosis factor-alpha (TNF-alpha). LAM also modulated intra-hepatic immune cells: it lowered the occurrence of peroxidase-positive cells (corresponding to monocytes/neutrophils) and, in contrast, it increased the number of ED2-positive cells, corresponding to resident hepatic macrophages, i.e. Kupffer cells. In conclusion, the hepatoprotective effect of marine beta (1-3) glucan during endotoxic shock may be linked to its immunomodulatory properties. We propose that both lower recruitment of inflammatory cells inside the liver tissue and lower secretion of inflammatory mediators play a role in the tissue protective effect of LAM. These effects could be due to a direct effect of beta-glucan on immune cells, or to an indirect effect through their dietary fibre properties (fermentation in the gut).
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PMID:Dietary supplementation with laminarin, a fermentable marine beta (1-3) glucan, protects against hepatotoxicity induced by LPS in rat by modulating immune response in the hepatic tissue. 1827 7

It has been proposed that proinflammatory mechanisms are involved in the pathogenesis of brain edema in acute liver failure (ALF). The aim of this study was to assess the contribution of cerebral inflammation to the neurologic complications of ALF and to assess the antiinflammatory effect of mild hypothermia. Upregulation of CD11b/c immunoreactivity, consistent with microglial activation, was observed in the brains of ALF rats at coma stages of encephalopathy. Interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) mRNAs were increased two to threefold in the brains of ALF rats compared with that in sham-operated controls. The magnitude of increased expression of proinflammatory cytokines in the brain was correlated with the progression of encephalopathy and the onset of brain edema. Significant increases in IL-1beta, IL-6, and TNF-alpha levels were also found in the sera and cerebrospinal fluid (CSF) of these animals. Mild hypothermia delayed the onset of encephalopathy, prevented brain edema, and concomitantly attenuated plasma, brain, and CSF proinflammatory cytokines. These results show that experimental ALF leads to increases in brain production of proinflammatory cytokines, and afford the first direct evidence that central inflammatory mechanisms play a role in the pathogenesis of the cerebral complications of ALF. Antiinflammatory agents could be beneficial in the management of these complications.
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PMID:Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia. 1925 10

Leptin is often regarded as a mediator of fever, even though an in-depth analysis of the dose-dependent effects of leptin on body temperature (T(b)), pro-inflammatory cytokines, and circulating leptin has never been performed. In the present study, such an analysis was performed in rats that were food deprived (lower baseline levels of leptin) or free feeding (higher baseline levels of leptin). In a relatively cool environment (22 degrees C), rats deprived of food for 24 h exhibited mild (approximately 0.5 degrees C) hypothermia. Leptin infusion (250 microg/kg iv) elevated the T(b) of the food-deprived rats to a normothermic level, an effect that peaked (120 min post-infusion) when plasma leptin was at a level (approximately 8 ng/mL) often found in leptin-responsive subjects. Increasing the leptin dose to 1000 microg/kg did not produce any further (febrile) elevation in the T(b) of food-deprived rats. The anti-hypothermic effect of leptin in food-deprived rats was not associated with any rise in the plasma levels of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. In free-feeding rats kept in a cooler (22 degrees C) or warmer (28 degrees C) environment, leptin infusion failed to alter T(b) or to produce any surge in plasma TNF-alpha or IL-6, even when the dose infused (3500 microg/kg iv) resulted in excessive, non-physiological rises in plasma leptin (approximately 542 ng/mL at 30 min; approximately 75 ng/mL at 120 min post-infusion). In contrast, free-feeding rats in the same experimental set-up were able to respond to a low dose (2 microg/kg iv) of IL-1beta with a typical biphasic fever, which was associated with surges in plasma TNF-alpha and IL-6. Collectively, our data show that an acute rise in plasma leptin to a level within or fairly above the physiological range does not induce fever. These results challenge the idea that leptin may be a mediator of fever.
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PMID:A reappraisal on the ability of leptin to induce fever. 1932 Nov 49

Although hypothermia is one of the most robust neuroprotectants clinically available, its underlying mechanisms remain unclear. Through microarray gene expression analysis, we previously identified several key molecules potentially involved in the efficacy of hypothermia in a 2h middle cerebral artery occlusion (MCAO) rat model, including cytokine and chemokine genes. The present study demonstrated that the expressions of 2 genes, macrophage inflammatory protein-3alpha (MIP-3alpha) and its receptor, CC-chemokine receptor 6 (CCR6), were upregulated in the model and were suppressed by hypothermia. To investigate the role of cerebral MIP-3alpha, it was administered into the rat striatum; dose- and time-dependent induction of CCR6 gene expression was observed. Interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha injection also induced sequential expressions of MIP-3alpha and CCR6. MIP-3alpha was found to be produced by proinflammatory cytokines in rat astrocytes, while it was suppressed by hypothermia. In turn, MIP-3alpha stimulated IL-1beta and inducible nitric oxide synthase expressions in rat microglia and rat brains. Furthermore, intracerebroventricular administration of an anti-rat MIP-3alpha-neutralizing antibody significantly reduced the infarct in MCAO rat brains. These findings suggest that MIP-3alpha plays a pivotal role in inflammatory cascades in ischemic brains, and may be a novel therapeutic target for cerebral ischemia.
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PMID:Macrophage inflammatory protein-3alpha plays a key role in the inflammatory cascade in rat focal cerebral ischemia. 1942 85

We reported a girl with HHV-6 infection associated with both acute encephalopathy with biphasic seizures and late reduced diffusion, and hemophagocytic syndrome. She had a prolonged convulsion after a one-day history of febrile illness. Cerebrospinal fluid or brain CT showed no abnormalities on admission and her consciousness was recovered on the next day. However, a prolonged seizure and deterioration of consciousness appeared on the sixth day of illness. Diffusion-weighted images revealed marked reduction of water diffusion in the bilateral frontal areas. HHV-6 infection was virologically proven by polymerase chain reaction. She was treated with gamma-globulin, steroid pulse therapy, and brain hypothermia. In addition, decrease in white blood cells and platelet counts, and elevation of liver enzymes and ferritin were noted on the fourth day of illness. Hemophagocytic macrophages were revealed by bone marrow aspiration on the sixth day. Her hematological and blood chemistry abnormalities recovered gradually after steroid pulse therapy. An elevation of interleukin-6, -8, and -10, and tumor necrosis factor in the serum and that of interleukin-4, -6, and-8 in the cerebrospinal fluid were observed at the onset of a late seizure. These facts suggested that hypercytokinemia will be related to the pathogenesis of acute encephalopathy of our patient.
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PMID:Acute encephalopathy with biphasic seizures and late reduced diffusion associated with hemophagocytic syndrome. 1955 82

Nitrite (NO(2)(-)), previously viewed as a physiologically inert metabolite and biomarker of the endogenous vasodilator NO, was recently identified as an important biological NO reservoir in vasculature and tissues, where it contributes to hypoxic signaling, vasodilation, and cytoprotection after ischemia-reperfusion injury. Reduction of nitrite to NO may occur enzymatically at low pH and oxygen tension by deoxyhemoglobin, deoxymyoglobin, xanthine oxidase, mitochondrial complexes, or NO synthase (NOS). We show that nitrite treatment, in sharp contrast with the worsening effect of NOS inhibition, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in a mouse shock model induced by a lethal tumor necrosis factor challenge. Mechanistically, nitrite-dependent protection was not associated with inhibition of mitochondrial complex I activity, as previously demonstrated for ischemia-reperfusion, but was largely abolished in mice deficient for the soluble guanylate cyclase (sGC) alpha1 subunit, one of the principal intracellular NO receptors and signal transducers in the cardiovasculature. Nitrite could also provide protection against toxicity induced by Gram-negative lipopolysaccharide, although higher doses were required. In conclusion, we show that nitrite can protect against toxicity in shock via sGC-dependent signaling, which may include hypoxic vasodilation necessary to maintain microcirculation and organ function, and cardioprotection.
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PMID:Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner. 1993 18

Despite the widespread interest in the clinical applications of hypothermia, the cellular mechanisms of hypothermia-induced neuroprotection have not yet been clearly understood. Therefore, the aim of this study was to elucidate the cellular effects of clinically relevant hypothermia and rewarming on the morphological and functional characteristics of microglia. Microglial cells were exposed to a dynamic cooling and rewarming protocol. For stimulation, microglial cells were treated with 1 microg/mL lipopolysaccharide (LPS). We found that hypothermia led to morphological changes from ramified to ameboid cell shapes. At 2 h after hypothermia and rewarming, microglial cells were again ramified with extended branches. Moreover, we found enhanced cell activation after rewarming, accompanied by increased phagocytosis and adenosine triphosphate consumption. Interestingly, hypothermia and rewarming led to a time-dependent significant up-regulation of the anti-inflammatory cytokines interleukin-10 and interleukin-1 receptor antagonist in stimulated microglial cells. This is in line with the reduced proliferation and time-dependent down-regulation of the pro-inflammatory cytokines tumor necrosis factor-alpha and monocyte chemotactic protein-1 in comparison to normothermic control cells after LPS stimulation. Furthermore, degradation of the inhibitor of the nuclear transcription factor-kappaB (IkappaB-alpha) was diminished and delayed under conditions of cooling and rewarming in LPS-stimulated microglial cells. Thus, our results show that hypothermia and rewarming activate microglial cells, increase phagocytosis and shift the balance of cytokine release in stimulated microglial cells towards the anti-inflammatory cytokines. This could be a new cellular mechanism of hypothermia-induced neuroprotection mediated by activated microglial cells.
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PMID:Mechanisms of hypothermia-induced cell protection mediated by microglial cells in vitro. 2037 79

Septic shock is associated with life-threatening vasodilation and hypotension. To cause vasodilation, vascular endothelium may release nitric oxide (NO), prostacyclin (PGI2), and the elusive endothelium-derived hyperpolarizing factor (EDHF). Although NO is critical in controlling vascular tone, inhibiting NO in septic shock does not improve outcome, on the contrary, precipitating the search for alternative therapeutic targets. Using a hyperacute tumor necrosis factor (TNF)-induced shock model in mice, we found that shock can develop independently of the known vasodilators NO, cGMP, PGI2, or epoxyeicosatrienoic acids. However, the antioxidant tempol efficiently prevented hypotension, bradycardia, hypothermia, and mortality, indicating the decisive involvement of reactive oxygen species (ROS) in these phenomena. Also, in classical TNF or lipopolysaccharide-induced shock models, tempol protected significantly. Experiments with (cell-permeable) superoxide dismutase or catalase, N-acetylcysteine and apocynin suggest that the ROS-dependent shock depends on intracellular (*)OH radicals. Potassium channels activated by ATP (K(ATP)) or calcium (K(Ca)) are important mediators of vascular relaxation. While NO and PGI2-induced vasodilation involves K(ATP) and large-conductance BK(Ca) channels, small-conductance SK(Ca) channels mediate vasodilation induced by EDHF. Interestingly, also SK(Ca) inhibition completely prevented the ROS-dependent shock. Our data thus indicate that intracellular (*)OH and SK(Ca) channels represent interesting new therapeutic targets for inflammatory shock. Moreover, they may also explain why antioxidants other than tempol fail to provide survival benefit during shock.
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PMID:Reactive oxygen species and small-conductance calcium-dependent potassium channels are key mediators of inflammation-induced hypotension and shock. 2049 72

Sepsis, characterized by a systemic inflammatory state that is usually related to Gram-negative bacterial infection, is a leading cause of death worldwide. Although the annual incidence of sepsis is still rising, the exact cause of Gram-negative bacteria-associated sepsis is not clear. Outer membrane vesicles (OMVs), constitutively secreted from Gram-negative bacteria, are nano-sized spherical bilayered proteolipids. Using a mouse model, we showed that intraperitoneal injection of OMVs derived from intestinal Escherichia coli induced lethality. Furthermore, OMVs induced host responses which resemble a clinically relevant condition like sepsis that was characterized by piloerection, eye exudates, hypothermia, tachypnea, leukopenia, disseminated intravascular coagulation, dysfunction of the lungs, hypotension, and systemic induction of tumor necrosis factor-alpha and interleukin-6. Our study revealed a previously unidentified causative microbial signal in the pathogenesis of sepsis, suggesting OMVs as a new therapeutic target to prevent and/or treat severe sepsis caused by Gram-negative bacterial infection.
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PMID:Outer membrane vesicles derived from Escherichia coli induce systemic inflammatory response syndrome. 2059 24


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