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)

Local cooling protects against TNF-alpha-induced injury by attenuating inflammation-associated microcirculatory dysfunction and leukocytic response. Mechanisms of protection, however, are not fully understood. We studied whether the metabolites of the HO and NOS pathway, exerting potent vasodilatory, antioxidant, and anti-apoptotic properties, are involved in tissue cryoprotection. In animals pretreated with L-NAME or SnPP-IX, cooling-associated abrogation of TNF-alpha-induced microcirculatory dysfunction was abolished. Combined L-NAME/SnPP-IX pretreatment did not cause greater blunting than seen when each mediator system was inhibited separately. In SnPP-IX- but not L-NAME-pretreated animals, transient hypothermia failed to reduce TNF-alpha-mediated leukocyte adherence. Vice versa, treatment of TNF-alpha-exposed animals with either the NO donor l-arginine or the HO-1 inductor hemin mimicked cooling-associated tissue protection except for failure of l-arginine to abrogate the inflammatory leukocyte response. The efficiency of cooling to inhibit TNF-alpha-induced apoptotic cell death was blunted in SnPP-IX-, L-NAME-, and SnPP-IX/L-NAME-pretreated animals. Coadministration of Trolox in SnPP-IX-treated animals partly attenuated leukocyte adherence and cell apoptosis, implying that the HO pathway metabolite biliverdin contributes to the salutary effects of cooling. Thus, our study provides evidence that metabolites of the HO and the NOS pathway mediate the cooling-associated protection of inflamed tissue. Biliverdin rather than CO and NO mediates the anti-inflammatory action, whereas a coordinated function of the gaseous monoxides prevents microcirculatory dysfunction and apoptotic cell death.
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PMID:Heme oxygenase and nitric oxide synthase mediate cooling-associated protection against TNF-alpha-induced microcirculatory dysfunction and apoptotic cell death. 1255 96

The effects of nimesulide and diclofenac on lipopolysaccharide (LPS)-induced rectal temperature changes and serum tumour necrosis factor (TNF)-alpha elevation were investigated in rats. LPS (Escherichia coli O111:B4; 50 microg/kg, intraperitoneally) produces a dual body temperature response, in which initial hypothermia precedes fever. Serum TNF-alpha levels rise during the initial phase of the induced hypothermia. Nimesulide, a preferential inhibitor of cyclooxygenase-2 (0.05, 0.5 or 1 mg/kg, subcutaneously) completely abolished the hypothermia, resulting in an acceleration of the fever phase. However, the peak and plateau phases of fever were not changed by nimesulide treatment. Nimesulide (0.5 mg/kg) partially prevented serum TNF-alpha elevation. The non-selective cyclooxygenase inhibitor diclofenac inhibited hypothermia at all doses tested (0.03, 0.3 or 3 mg/kg, subcutaneously) although fever was completely abolished at the 3 mg/kg dose only. Diclofenac also partially abolished the elevation in serum TNF-alpha levels, but at the highest dose only (3 mg/kg). These data suggest that nimesulide and diclofenac can preferentially inhibit LPS-induced hypothermia at doses that do not abolish fever in rats. Both these drugs also reduced elevated TNF-alpha levels, a fact which may, at least partly, explain the antihypothermic effect of nimesulide.
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PMID:Nimesulide and diclofenac inhibit lipopolysaccharide-induced hypothermia and tumour necrosis factor-alpha elevation in rats. 1257 19

Nuclear factor-kappaB (NFkappaB) is a transcription factor that is activated after cerebral ischemia. NFkappaB activation leads to the expression of many inflammatory genes involved in the pathogenesis of stroke. The authors previously showed that mild hypothermia is protective even when cooling begins 2 h after stroke onset. In the present study, they examined the influence of hypothermia on NFkappaB activation. Rats underwent 2 h of transient middle cerebral artery occlusion. Brains were cooled to 33 degrees C immediately after or 2 h after occlusion, and maintained for 2 h. After normothermic ischemia (brain temperature at 38 degrees C), NFkappaB cytoplasmic expression, nuclear translocation, and binding activity were observed as early as 2 h in the ischemic hemisphere and persisted at 24 h. Hypothermia decreased NFkappaB translocation and binding activity but did not alter overall expression. Hypothermia also affected the levels of NFkappaB regulatory proteins by suppressing phosphorylation of NFkappaB's inhibitory protein (IkappaB-alpha) and IkappaB kinase (IKK-gamma) and decreasing IKK activity, but did not alter overall IKK levels. Hypothermia suppressed the expression of two NFkappaB target genes: inducible nitric oxide synthase and TNF-alpha. These data suggest that the protective effect of hypothermia on cerebral injury is, in part, related to NFkappaB inhibition due to decreased activity of IKK.
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PMID:Mild hypothermia inhibits nuclear factor-kappaB translocation in experimental stroke. 1277 74

Accidental hypothermia is a common companion of trauma/haemorrhage, and several clinical studies have identified reduced body temperature as an independent risk predisposing to increased morbidity and mortality. Accordingly, the majority of trauma care guidelines prescribe early and aggressive rewarming of hypothermic patients. Enzyme reactions are generally downregulated at temperatures below 37 degrees C, including most of those responsible for the inflammatory response. The rationale for adhering to these recommendations uncritically may therefore be questioned. In a rat model of mild hypothermia and haemorrhagic shock we wanted to compare the influence of rapid rewarming with persistently reduced temperature on the synthesis of early inflammatory mediators and organ function. Thirty-four male albino Sprague-Dawley rats were studied. Withdrawal of 2.5 ml blood/100 g body weight was performed over 10 min, with simultaneous reduction of body temperature to 32.5-33.5 degrees C. Seventy-five minutes after initiation of bleeding, two-thirds of the shed blood was retransfused. One group (n=17) was rewarmed to normothermia, the other (n=17) was kept hypothermic. The study was terminated after an observation period of 2 h. At the end of the study the rewarmed animals had a significantly lower mean arterial pressure, higher heart rate, higher synthesis of reactive oxygen species from peritoneal phagocytes, increased circulating levels of nitric oxide, and higher values of the organ markers aspartate aminotransferase and urea. The pro-inflammatory cytokines TNF-alpha and IL-6, the anti-inflammatory cytokine IL-10, the organ markers alanine aminotransferase, alpha-glutathione S-transferase and creatinine, as well as organ injury scores were equal in both groups. Three rewarmed rats died prematurely, versus one hypothermic animal. In conclusion, the results suggest that during the early stages after haemorrhagic shock, rapid rewarming from mild hypothermia may have unfavourable effects both on basic haemodynamic variables, and on the internal inflammatory environment of cells and tissues.
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PMID:Rapid rewarming after mild hypothermia accentuates the inflammatory response after acute volume controlled haemorrhage in spontaneously breathing rats. 1286 16

Hypothermia is one of the prominent features of the acute phase response to endotoxin (LPS). This study was undertaken to elucidate the effects of the COX-inhibitor Indomethacin (INDO) and the selective FLAP inhibitor MK-886 on LPS-induced hypothermia, mortality and increase in production of hypothalamic prostaglandin E(2) (PGE(2)) and leukotriene during endotoxemia. It has been demonstrated that INDO and MK-886 significantly attenuate the hypothermia induced by LPS, but MK-886 has a lesser (protective) effect than INDO. Only INDO was found to attenuate significantly the hyperthermic response to LPS. Furthermore, INDO significantly reduced the elevation in hypothalamic PGE(2) levels. MK-886 significantly reduced the elevation in hypothalamic leukotriene production only when LPS was given in a dose of 1mg/kg. Both drugs failed to reduce the elevation in plasma TNF-alpha and mortality induced by LPS. We conclude that in rats, febrile response to endotoxin involves many inflammatory mediators. However, it seems that PGE(2) and leukotrienes do not have a pivotal role in the mechanism of LPS-induced mortality.
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PMID:Involvement of eicosanoids in the hypothermic response to lipopolysaccharide during endotoxemia in rats. 1464 81

While moderate hypothermia is protective against ischemic cardiac and brain injury, it is associated with much higher mortality in patients with sepsis. We previously showed that in vitro exposure to moderate hypothermia (32 degrees C) delays the induction and prolongs the duration of TNF-alpha and IL-1beta secretion by lipopolysaccharide (LPS)-stimulated human mononuclear phagocytes. In the present study, we extended these observations by showing that moderate hypothermia exerts effects on TNF-alpha and IL-1beta generation in the human THP-1 monocyte cell line that are similar to those that we previously found in primary cultured monocytes; that hypothermia causes comparable changes in cytokine generation stimulated by zymosan, toxic shock syndrome toxin-1, and LPS; and that hypothermia causes similar changes in TNF-alpha and IL-1beta mRNA accumulation. TNF-alpha mRNA half-life, determined after transcriptional arrest with actinomycin D, was not significantly prolonged by lowering incubation temperature from 37 to 32 degrees C, suggesting that hypothermia modifies TNF-alpha gene transcription. This finding was further supported by reporter gene studies showing a threefold increase in activity of the human TNF-alpha promoter at 32 vs. 37 degrees C. Electrophoretic mobility shift assay revealed that hypothermia prolonged NF-kappaBeta activation, identifying a potential role for this transcription factor in mediating the effects of hypothermia on TNF-alpha and IL-1beta production. Delayed reexpression of the inhibitor IkappaBalpha, shown by Northern blotting and immunoblotting, may account in part for the prolonged NF-kappaBeta activation at 32 degrees C. Augmentation of NF-kappaBeta-dependent gene expression during prolonged exposure to hypothermia may be a common mechanism leading to increased lethality in sepsis, late-onset systemic inflammatory response syndrome after accidental hypothermia, and neuroprotection after ischemia.
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PMID:Hypothermia prolongs activation of NF-kappaB and augments generation of inflammatory cytokines. 1507 Aug 15

Mild hypothermia impairs resistance to infection and, reportedly, impairs phagocytosis and oxidative killing of unopsonized bacteria. We evaluated various functions at 33 degrees-41 degrees C in neutrophils taken from volunteers. Adhesion on endothelial cells was determined using light microscopy. Adhesion molecule expression and receptors, phagocytosis, and release of reactive oxidants were assessed using flow cytometric assays. Adhesion protein CD11b expression on resting neutrophils was temperature-independent. However, up-regulation of CD11b with tumor necrosis factor (TNF)-alpha was increased by hypothermia and decreased with hyperthermia. Neutrophil adhesion to either resting or activated endothelial cells was not temperature-dependent. Bacterial uptake was inversely related to temperature, more so with Escherichia coli than Staphylococcus aureus. Temperature dependence of phagocytosis occurred only wi thopsonized bacteria. Hypothermia slightly increased N-formyl-L-methionyl-L-leucyl-phenylalanine receptors on neutrophils: hyperthermia decreased expression, especially with TNF-alpha. N-formyl-L-methionyl-L-leucyl-phenylalanine-induced H2O2 production was inversely related to temperature, especially in the presence of TNF-alpha. Conversely, phorbol-13-myristate-12-acetate, an activator of protein kinase C, induced an extreme and homogenous release of reactive oxidants that increased with temperature. In contrast to nonreceptor-dependent phagocytosis and oxidative killing, several crucial receptor-dependent neutrophil activities show temperature-dependent regulation, with hypothermia increasing function. The temperature dependence of neutrophil function is thus more complicated than previously appreciated.
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PMID:Mild hyperthermia down-regulates receptor-dependent neutrophil function. 1528 45

Obese (f/f) Koletsky rats lack the leptin receptor (LR), whereas their lean (F/?) counterparts bear a fully functional LR. By using f/f and F/? rats, we studied whether the LR is involved in lipopolysaccharide (LPS)-induced fever and hypothermia. The body temperature responses to LPS (10 or 100 microg/kg iv) were measured in Koletsky rats exposed to a thermoneutral (28 degrees C) or cool (22 degrees C) environment. Rats of both genotypes responded to LPS with fever at 28 degrees C and with dose-dependent hypothermia at 22 degrees C. The fever responses of the f/f and F/? rats were identical. The hypothermic response of the f/f rats was markedly prolonged compared with that of the F/? rats. The prolonged hypothermic response to LPS in the f/f rats was accompanied by enhanced NF-kappaB signaling in the hypothalamus and an exaggerated rise in the plasma concentration of tumor necrosis factor (TNF)-alpha. The f/f rats did not respond to LPS with an increase in the plasma concentration of corticosterone or adrenocorticotropic hormone, whereas their F/? counterparts did. The hypothermic response to TNF-alpha (80 microg/kg iv) was markedly prolonged in the f/f rats. These data show that the LR is essential for the recovery from LPS hypothermia. LR-dependent mechanisms of the recovery from LPS hypothermia include activation of the anti-inflammatory hypothalamo-pituitary-adrenal axis, inhibition of both the production and hypothermic action of TNF-alpha, and suppression of inflammatory (via NF-kappaB) signaling in the hypothalamus.
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PMID:A new function of the leptin receptor: mediation of the recovery from lipopolysaccharide-induced hypothermia. 1538 70

Anesthetized rams envenomed s.c. with 40 microg/kg Tityus discrepans scorpion venom developed fasciculation, hypothermia, polyuria, pulmonary wet rales, tachypnea, respiratory distress and arrhythmia. Rams developed a cascade of inflammation reactions, characterized by activation of macrophages, fibroblasts and neutrophils, neutrophil infiltration and aggregation, vasculitis, arteritis and abundant fibrin deposition. At the inoculation site, venom was detected by immunohistochemistry in the extra cellular matrix, lymphatic vessels' and venules' lumen, inside macrophages and surrounding nerves. Extra cellular matrix was degraded at the inoculation site perhaps by activated neutrophils. Envenoming produced hepatocytes with Mallory body-like vacuoles which may be due to the increased plasmatic levels of TNF-alpha and IL6. Venom produced degranulation and vacuolization of acinary cells as well as interstitial swelling and necrosis. Necrosis of the Langerhan's islets occurred occasionally. Lungs showed the most deleterious effects developing wall collapse and necrosis, diffuse injury of the alveolar capillary barrier, interstitial and alveolar fibrin deposits with strong neutrophil infiltration. Massive infiltration of lymphocytes and macrophage occurred in the intestinal submucose, to the point that it modified villi and intestinal folding morphology. Envenomation developed a marked leukocyte aggregation surrounding nerves at the inoculation site. This study reveals that beyond its neurotoxicity, Tityus venom produces a severe and widespread inflammatory syndrome, expressed as histopathological changes at the site of inoculation, as well as in remote organs such as pancreas, lungs, intestine and liver. Our results suggest that not all remote targets are directly affected by the venom but that, as proposed earlier, are modified by inflammation by products produced elsewhere.
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PMID:Histopathological changes and inflammatory response induced by Tityus discrepans scorpion venom in rams. 1553 Sep 67

Hypothermic preservation can increase hepatocyte sensitivity to various insults. Here we studied the hypothesis that hepatocytes are injured by manipulation with cold-preserved liver. Livers from Wistar rats were divided into two groups. In the 1st group (n = 6) the livers were placed after harvesting into a polyethylene (PE) bag. After the preservation period they were placed into the perfusion chamber--developed in our laboratory. Connection of livers from PE bag to the perfusion chamber required a contact manipulation with the liver. This contact manipulation was eliminated in the second group of livers (n = 6) by using the perfusion chamber for preservation. Lavage and perfusion were done in both groups under the same conditions. We found in the lavage solution of livers of the 1st group 2-times more LDH and 3.7-times higher release of TNF-alpha compared to the 2nd group. Further, bile flow of livers from the 1st group during reperfusion was significantly lower compared to the 2nd group (0.179 +/- 0,12 vs 0.398 +/- 0.15 ml/min/g liver). Manipulation with hypothermic liver leads to hepatocyte injury. Our new model of chamber can protect hypothermic liver against manipulation injury and can allow to perform physiological and pharmacological experiments on liver ex vivo.
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PMID:[Protection of hypothermic rat liver against gentle manipulation injury]. 1570 37


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