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)

Pro-inflammatory cytokines and nitric oxide (NO) are considered responsible for exacerbating brain injury. Activated microglia produce these potentially cytotoxic factors during neuron destruction. The beneficial effects of hypothermia on neuroprotection are considered to be due, in part, to suppression of post-injury inflammatory factors by microglia. However, the underlying mechanisms remain unclear. In particular, the hypothermia's role in modulating anti-inflammatory cytokines is unknown. We examined whether altering culture temperature modifies microglial production of cytokines and NO. Microglia isolated from neonatal rats were cultured with 1 microg/mL lipopolysaccharide (LPS) under hypothermic, normothermic, and hyperthermic conditions for 72 h. Interleukin (IL)-6 and IL-10 levels in supernatants were measured by enzyme-linked immunosorbent assay (ELISA). NO production was analyzed by colorimetric assay of nitrite accumulated in the medium. Compared to normothermia, hypothermia decreased LPS-induced IL-6 production at 6 h of culture. In contrast, hyperthermia reduced IL-6 production throughout culture. IL-10 production was reduced by hypothermia but augmented by hyperthermia at 24-72 h. NO production was reduced by hypothermia throughout culture, while no significant differences in NO production were observed between normothermia and hyperthermia. In this study, hypothermia reduced production of IL-6, IL-10, and NO by LPS-activated microglia, suggesting that the neuroprotective effects of hypothermia might involve not only the inhibition of inflammatory factors, but also anti-inflammatory factor(s). Hyperthermia specifically increased IL-10 production in these cells. These temperature-dependent changes in IL-10 production may imply an important clinical marker for this cytokine in hypothermia-related neuronal protection and in hyperthermia-related neuronal injury.
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PMID:IL-10 production is reduced by hypothermia but augmented by hyperthermia in rat microglia. 1853 91

Inflammatory response with cytokine release is reported to correlate with clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). In selected cases, hypothermia and barbiturate coma are applied as means for neuroprotection after severe SAH. Hypothermia and high-dose barbiturate are reported to attenuate the inflammatory response. In this pilot study, we assessed the effect of the combined therapy on the inflammatory response. In 15 patients with SAH, daily cerebrospinal fluid (CSF) and plasma samples were collected. Interleukin (IL)-6, tumor necrosis factor alpha (TNF-alpha), IL-1beta, systemic leukocyte, and leukocyte counts in the CSF were quantified. Group 1 represented 7 cases treated with combined therapeutic hypothermia (33 degrees C) and barbiturate coma. Group 2 represented 8 cases without combined therapy. Compared with the systemic levels, all cases showed higher cytokine levels in the CSF. Mean IL-6 level in the CSF was significantly lower in group 1 (P<0.001). The ratio between IL-6 levels in the CSF and plasma, as a parameter for intrathecal synthesis, was significantly lower in group 1 (P=0.014). Mean CSF and systemic levels of TNF-alpha of group 1 were significantly higher compared with group 2 (P=0.009 and P<0.001). The mean systemic IL-1beta level was significantly lower in group 1 (P<0.001), as well as the leukocyte counts, both, systemic and in the CSF (P<0.001 and P=0.032). The present data show a most pronounced decrease of IL-6 levels in the CSF, beside decrease in systemic IL-1beta levels, systemic leukocyte counts, and CSF leukocyte counts in group 1, which would be expected to reflect an attenuation of inflammatory response. The impact and role of TNF-alpha remains unclear.
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PMID:Combined therapeutic hypothermia and barbiturate coma reduces interleukin-6 in the cerebrospinal fluid after aneurysmal subarachnoid hemorrhage. 1858 Mar 50

MuS110 is a BiTE antibody bispecific for murine EpCAM (CD326) and murine CD3. A recent study has shown that microS110 has significant anti tumor activity at well-tolerated doses as low as 5 microg/kg in orthotopic breast and lung cancer models (Amann et al. in Cancer Res 68:143-151, 2008). Here, we have explored the safety profile of microS110 at higher doses. Escalation to 50 microg/kg microS110 caused in mice transient loss of body weight, and transient piloerection, hypomotility, hypothermia and diarrhoea. These clinical signs coincided with serum peaks of TNF-alpha, IL-6, IL-2, IFN-gamma and IL-4, and an increase of surface markers for T cell activation. Because activation of T cells in response to BiTE antibodies is typically dependent on target cells, we analyzed mouse blood for the presence of EpCAM(+) cells. Various mouse strains presented with a subpopulation of 2-3% EpCAM(+) blood cells, mostly B and T lymphocytes, which was not detected in human blood samples. In vitro experiments in which the number of EpCAM(+) cells in blood samples was either reduced or increased suggested that both T cell activation and cytokine release in response to microS110 was dependent on the number of target-expressing cells. In support for a role of EpCAM(+) lymphocytes in the observed side effects, reduction of EpCAM(+) blood cells in mice via a low-dose pre treatment with microS110 dramatically increased the tolerability of animals up to at least 500 microg/kg of the BiTE antibody. This high tolerability to microS110 occurred in the presence of non-compromised T cells. No damage to EpCAM(+) epithelial tissues was evident from histopathological examination of animals daily injected with 100 microg/kg microS110 for 28 days. In summary, these observations suggest that side effects of microS110 in mice were largely caused by an acute T cell activation that was triggered by a subpopulation of EpCAM(+) lymphocytes. Because humans have extremely low numbers of EpCAM(+) cells in blood, this toxicity of an EpCAM-specific BiTE may be specific for mice.
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PMID:Therapeutic window of an EpCAM/CD3-specific BiTE antibody in mice is determined by a subpopulation of EpCAM-expressing lymphocytes that is absent in humans. 1859 18

Hypothermia is a standard method for organ protection during cardiac surgery in children. However, the mechanisms of hypothermia-induced cell protection have not yet been clearly established. Therefore, the aim of our studies was to elucidate molecular effects of clinically relevant mild and deep hypothermia on endothelial cells. The endothelium plays a pivotal role in the interaction between blood cells and actively participates in complex inflammatory events. We isolated primary human umbilical vein endothelial cells (HUVEC) and investigated cell viability, proliferation and inflammatory characteristics after TNF-alpha stimulation under mild (32 degrees C) and deep (17 degrees C) hypothermia in comparison to normothermia (37 degrees C). As a protective mechanism of endothelial cells kept under hypothermic conditions we found a significant upregulation of the antiapoptotic protein Bcl-2, resulting in the same cell viability under hypothermic conditions. Unexpectedly we demonstrated significantly higher IL-6 release after 6h of mild hypothermia. In contrast, hypothermia diminished inflammatory chemokines such as IL-8, MCP-1 and COX-2 protein expression which could lead to reduced leukocyte recruitment under hypothermia. Underlying mechanisms of this downregulation were found to be reduced ERK 1/2 phosphorylation and incomplete IkappaB-alpha degradation resulting in reduced NFkappaB-dependent proinflammatory gene expression. The upregulation of Bcl-2 protein and the higher IL-6 release after 6h of mild hypothermia are new and interesting cellular mechanisms of hypothermia in endothelial cell biology. Both factors may play a major role as cell protective mechanisms in hypothermia.
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PMID:Hypothermia downregulates inflammation but enhances IL-6 secretion by stimulated endothelial cells. 1879 Jun 95

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

To protect immature organ systems during corrective cardiac surgery, patients are cooled to a minimal temperature of 17 degrees C during cardiopulmonary bypass (CPB). However hypothermic CPB triggers the whole body inflammatory response and results in unwanted prolonged inflammation. The present study was designed to clarify the hypothermia and rewarming induced mechanisms and examine interventional pharmacological strategies that could prevent prolonged inflammation. Stimulated primary human umbilical vein endothelial cells (HUVECs) were exposed to a dynamic temperature protocol analogous to clinical settings. Furthermore endothelial cells were pretreated with methylprednisolone and/or tacrolimus as well as with MAPK inhibitors (SB203580, U0126 and SP600125). Cell viability, expression of IL-6 and ERK 1/2, p38 and SAPK/JNK were investigated. Stimulated endothelial cells secreted significantly higher IL-6 protein 2h after rewarming in comparison to normothermic control cells. Moreover, dynamic temperature changes lead to increased MAPK phosphorylation. Only the combined pre-treatment with MP and TAC served to inhibit the IL-6 secretion. As intracellular signalling pathway we could demonstrate that SB203580 as specific p38 inhibitor most effectively down regulated the unwanted IL-6 release after cooling and rewarming. Therefore inhibition of p38 or components of the p38 pathway could be a promising and selective antiinflammatory therapeutic target after hypothermic CPB.
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PMID:Specific p38 inhibition in stimulated endothelial cells: a possible new anti-inflammatory strategy after hypothermia and rewarming. 1957 93

Tumor necrosis factor (TNF) is reputed to have very powerful antitumor effects, but it is also a strong proinflammatory cytokine. Injection of TNF in humans and mice leads to a systemic inflammatory response syndrome with major effects on liver and bowels. TNF is also a central mediator in several inflammatory diseases. We report that type I interferons (IFNs) are essential mediators of the lethal response to TNF. Mice deficient in the IFN-alpha receptor 1 (IFNAR-1) or in IFN-beta are remarkably resistant to TNF-induced hypothermia and death. After TNF injection, IFNAR-1(-/-) mice produced less IL-6, had less bowel damage, and had less apoptosis of enterocytes and hepatocytes compared with wild-type (WT) mice. Extensive gene expression analysis in livers of WT and IFNAR-1(-/-) mice revealed a large deficiency in the response to TNF in the knockout mice, especially of IFN-stimulated response element-dependent genes, many of which encode chemokines. In livers of IFNAR-1(-/-) mice, fewer infiltrating white blood cells (WBCs) were detected by immunohistochemistry. Deficiency of type I IFN signaling provided sufficient protection for potentially safer therapeutic use of TNF in tumor-bearing mice. Our data illustrate that type I IFNs act as essential mediators in TNF-induced lethal inflammatory shock, possibly by enhancing cell death and inducing chemokines and WBC infiltration in tissues.
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PMID:Type I interferon drives tumor necrosis factor-induced lethal shock. 1968 27

Systemic inflammation gives rise to metabolic and behavioural changes, largely mediated by pro-inflammatory cytokines and prostaglandin production (PGE(2)) at the blood-brain barrier. Despite numerous studies, the exact biological pathways that give rise to these changes remains elusive. This study investigated the mechanisms underlying immune-to-brain communication following systemic inflammation using various anti-inflammatory agents. Mice were pre-treated with selective cyclo-oxygenase (COX) inhibitors, thromboxane synthase inhibitors or dexamethasone, followed by intra-peritoneal injection of lipopolysaccharide (LPS). Changes in body temperature, open-field activity, and burrowing were assessed and mRNA and/or protein levels of inflammatory mediators measured in serum and brain. LPS-induced systemic inflammation resulted in behavioural changes and increased production of IL-6, IL-1beta and TNF-alpha, as well as PGE(2) in serum and brain. Indomethacin and ibuprofen reversed the effect of LPS on behaviour without changing peripheral or central IL-6, IL-1beta and TNF-alpha mRNA levels. In contrast, dexamethasone did not alter LPS-induced behavioural changes, despite complete inhibition of cytokine production. A selective COX-1 inhibitor, piroxicam, but not the selective COX-2 inhibitor, nimesulide, reversed the LPS-induced behavioural changes without affecting IL-6, IL-1beta and TNF-alpha protein expression levels in the periphery or mRNA levels in the hippocampus. Our results suggest that the acute LPS-induced changes in burrowing and open-field activity depend on COX-1. We further show that COX-1 is not responsible for the induction of brain IL-6, IL-1beta and TNF-alpha synthesis or LPS-induced hypothermia. Our results may have implications for novel therapeutic strategies to treat or prevent neurological diseases with an inflammatory component.
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PMID:The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: Implications for a role of COX-1. 2114 93

This study aimed to analyze changes in nuclear factor-kappa B (NF-kappaB), inflammation factors, and macrophages in pulmonary tissue under deep hypothermia circulatory arrest (DHCA) at different time points, which can be used to infer the role of early macrophage activation and NF-kappaB activity in pulmonary injury. The possible pathogenic mechanisms of DHCA-induced pulmonary injury were investigated in this study to provide an experimental basis for clinical lung protective strategies. Piglets (n = 12) were randomly divided into 2 groups, with 6 piglets in each group. The control group had ambient temperature cardiopulmonary bypass (CPB), and the experimental group had DHCA. Both groups had conventional CPB with 30 min of parallel circulation. Changes in NF-kappaB and inflammatory factors were examined in each group at 6 different time points. At 0.5 h after ischemia-reperfusion, NF-kappaB expression in the nucleus of pulmonary tissue reached its peak, and brown-stained nuclei were mainly polymorphonuclear antibodies. At 1 h after ischemia-reperfusion, plasma tumor-necrosis factor (TNF)-alpha in the experimental group was significantly increased compared with that before reperfusion (P < 0.05). The plasma levels of interleukin (IL)-8 and IL-6 in the experimental group were significantly increased at 1.5 h after ischemia-reperfusion compared with the levels before reperfusion (P < 0.05). Early activation of NF-kappaB under DHCA might play an important role in DHCA-induced pulmonary injury.
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PMID:Evaluation of early macrophage activation and NF-kappaB activity in pulmonary injury caused by deep hypothermia circulatory arrest: an experimental study. 1995 73

Cigarette smoke exposure increases the risk of pulmonary and invasive infections caused by Streptococcus pneumoniae, the most commonly isolated organism from patients with community-acquired pneumonia. Despite this association, the mechanisms by which cigarette smoke exposure diminishes host defense against S. pneumoniae infections are poorly understood. In this study, we compared the responses of BALB/c mice following an intratracheal challenge with S. pneumoniae after 5 weeks of exposure to room air or cigarette smoke in a whole-body exposure chamber in vivo and the effects of cigarette smoke on alveolar macrophage phagocytosis of S. pneumoniae in vitro. Bacterial burdens in cigarette smoke-exposed mice were increased at 24 and 48 h postinfection, and this was accompanied by a more pronounced clinical appearance of illness, hypothermia, and increased lung homogenate cytokines interleukin-1beta (IL-1beta), IL-6, IL-10, and tumor necrosis factor alpha (TNF-alpha). We also found greater numbers of neutrophils in bronchoalveolar lavage fluid recovered from cigarette smoke-exposed mice following a challenge with heat-killed S. pneumoniae. Interestingly, overnight culture of alveolar macrophages with 1% cigarette smoke extract, a level that did not affect alveolar macrophage viability, reduced complement-mediated phagocytosis of S. pneumoniae, while the ingestion of unopsonized bacteria or IgG-coated microspheres was not affected. This murine model provides robust additional support to the hypothesis that cigarette smoke exposure increases the risk of pneumococcal pneumonia and defines a novel cellular mechanism to help explain this immunosuppressive effect.
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PMID:Cigarette smoke exposure impairs pulmonary bacterial clearance and alveolar macrophage complement-mediated phagocytosis of Streptococcus pneumoniae. 2000 40


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