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)

Tumor necrosis factor (TNF)-alpha, a cardinal molecule in the cascade of sepsis-induced host injury, binds to two distinct receptors: tumor necrosis factor receptor (TNFR) 1 and TNFR2. We used the cecal ligation and puncture model of polymicrobial sepsis to elucidate the role of these receptors in sepsis pathogenesis. Mice lacking TNFR1 had prolonged survival with less hypothermia, whereas mice lacking TNFR2-/- had shortened survival and more profound hypothermia than wild-type mice. TNFR1-/- and TNFR2-/- mice had increased serum concentrations of interleukin (IL) 1beta and total TNF-alpha (free plus receptor bound) compared with wild-type mice, but there were no differences in IL6 or IL10 concentrations. Furthermore, free TNF-alpha was markedly elevated in the serum and peritoneal fluid of mice lacking TNFR2, supporting a role for this receptor in regulating the concentration of TNF-alpha. Lastly, apoptosis of ileal crypt epithelial cells was increased in mice lacking TNFR1, but there were no differences in lymphocyte apoptosis. These data suggest that in sepsis, TNFR1 mediates much of the TNF-alpha-induced pathology, whereas TNFR2 mediates protective effects.
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PMID:Opposing effects of tumor necrosis factor receptor 1 and 2 in sepsis due to cecal ligation and puncture. 1580 53

LPS preparations cause a variety of body temperature (T(b)) responses: monophasic fever, different phases of polyphasic fever, and hypothermia. Conventional (c) LPS preparations contain highly active lipoprotein contaminants (endotoxin proteins). Whereas LPS signals predominantly via the Toll-like receptor (TLR) 4, endotoxin proteins signal via TLR2. Several TLR2-dependent responses of immunocytes to cLPS in vitro are triggered by endotoxin proteins and not by LPS itself. We tested whether any T(b) response to cLPS from Escherichia coli 055:B5 is triggered by non-TLR4-signaling contaminants. A decontaminated (d) LPS preparation (free of endotoxin proteins) was produced by subjecting cLPS to phenol-water reextraction. The presence of non-TLR4-signaling contaminants in cLPS (and their absence in dLPS) was confirmed by showing that cLPS (but not dLPS) induced IL-1beta expression in the spleen and increased serum levels of TNF-alpha and IL-1beta of C3H/HeJ mice; these mice bear a nonfunctional TLR4. Yet, both cLPS and dLPS caused cytokine responses in C3H/HeOuJ mice; these mice bear a fully functional TLR4. We then studied the T(b) responses to cLPS and dLPS in Wistar rats preimplanted with jugular catheters. At a neutral ambient temperature (30 degrees C), a low (0.1 microg/kg iv) dose of cLPS caused a monophasic fever, whereas a moderate (10 microg/kg iv) dose produced a polyphasic fever. In the cold (20 degrees C), a high (500 microg/kg iv) dose of cLPS caused hypothermia. All T(b) responses to dLPS were identical to those of cLPS. We conclude that all known T(b) responses to LPS preparations are triggered by LPS per se and not by non-TLR4-signaling contaminants of such preparations.
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PMID:Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se-- not by lipoprotein contaminants. 1586 Jun 47

Hypothermia (HT) has been associated with both beneficial and detrimental consequences in various pathophysiological states. While HT is generally thought to have anti-inflammatory and cytoprotective effects, we have previously shown that moderate in vitro HT prolongs TNF-alpha production by LPS-stimulated mononuclear phagocytes, in part by prolonging TNF-alpha gene transcription and activation of the pleiotropic transcription factor NF-kappaB. In this study, we have further characterized the effect of moderate (32 degrees C) and marked (28 degrees C) HT in human monocytic THP-1 cells by showing that even short (2 h) exposure to HT followed by a return to normothermic conditions for 22 h resulted in augmented and prolonged production of TNF-alpha. Production of heat shock protein 72 and activation of heat shock factor 1 are not affected by HT in these studies, suggesting that the effect is not part of a generalized stress response. Using immunoblotting, we have shown that HT augments phosphorylation of IKK-beta and IKK-alpha (up to an 8-fold increase at 28 degrees C and a 3.6-fold increase at 32 degrees C vs. 37 degrees C). Furthermore, nuclear accumulation of NF-kappaB p65 was significantly prolonged in hypothermic cells (1.4- and 2.5-fold more nuclear p65 at 2 and 4 h at 28 vs. 37 degrees C). Reexpression of IkappaB-alpha, which contributes to the termination of NF-kappaB-dependent transcription, was delayed several hours in HT-exposed cells. Thus we have shown that clinically relevant HT alters both cytosolic and nuclear events responsible for NF-kappaB activation and deactivation. Enhanced NF-kappaB activation may contribute to the immunomodulatory effects of HT in various clinical settings.
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PMID:Hypothermia enhances phosphorylation of I{kappa}B kinase and prolongs nuclear localization of NF-{kappa}B in lipopolysaccharide-activated macrophages. 1597 40

Transforming growth factor-beta (TGF-beta) is an important suppressor of inflammation. However, TGF-beta has also been found to promote secretion of inflammatory cytokines, and transgenic mice, which constitutively express TGF-beta in liver, have been found to be more susceptible to endotoxemia. To approach this apparent paradox, we investigated the role of hepatic TGF-beta1 in endotoxemia by utilising inducible TGF-beta1-transgenic mice that express TGF-beta1 under control of the C-reactive protein promoter. In contrast to non-transgenic littermates, administration of lipopolysaccharide (LPS) induced strongly increased expression of TGF-beta and acute phase proteins in the TGF-beta1-transgenic mice. Hepatic TGF-beta1-expression in the transgenic mice started an inflammatory cytokine cascade, marked by increased and prolonged secretion of TNF-alpha and IL-6 by hepatocytes. The inflammatory response of the TGF-beta1-transgenic mice to LPS was associated with high rates of mortality due to endotoxemic shock, marked by systemic hypotension and hypothermia. Endotoxemic shock was primarily mediated by TNF-alpha and IL-6, since inhibitory antibody to TNF-alpha or, more effectively, to IL-6 could reduce mortality in these mice. In conclusion, while TGF-beta-signalling to immune cells may suppress inflammatory effector function, TGF-beta-signalling to liver cells seems to promote LPS-stimulated secretion of inflammatory cytokines and to predispose for lethal endotoxemic shock.
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PMID:Hepatic over-expression of TGF-beta1 promotes LPS-induced inflammatory cytokine secretion by liver cells and endotoxemic shock. 1605 5

Elevated circulating cytokines are observed in heatstroke patients, suggesting a role for these substances in the pathophysiological responses of this syndrome. Typically, cytokines are determined at end-stage heatstroke such that changes throughout progression of the syndrome are poorly understood. We hypothesized that the cytokine milieu changes during heatstroke progression, correlating with thermoregulatory, hemodynamic, and tissue injury responses to heat exposure in the mouse. We determined plasma IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IFN-gamma, macrophage inflammatory protein-1alpha, TNF-alpha, corticosterone, glucose, hematocrit, and tissue injury during 24 h of recovery. Mice were exposed to ambient temperature of 39.5 +/- 0.2 degrees C, without food and water, until maximum core temperature (T(c,Max)) of 42.7 degrees C was attained. During recovery, mice displayed hypothermia (29.3 +/- 0.4 degrees C) and a feverlike elevation at 24 h (control = 36.2 +/- 0.3 degrees C vs. heat stressed = 37.8 +/- 0.3 degrees C). Dehydration ( approximately 10%) and hypoglycemia ( approximately 65-75% reduction) occurred from T(c,Max) to hypothermia. IL-1alpha, IL-2, IL-4, IL-12p70, IFN-gamma, TNF-alpha, and macrophage inflammatory protein-1alpha were undetectable. IL-12p40 was elevated at T(c,Max), whereas IL-1beta, IL-6, and IL-10 inversely correlated with core temperature, showing maximum production at hypothermia. IL-6 was elevated, whereas IL-12p40 levels were decreased below baseline at 24 h. Corticosterone positively correlated with IL-6, increasing from T(c,Max) to hypothermia, with recovery to baseline by 24 h. Tissue lesions were observed in duodenum, spleen, and kidney at T(c,Max), hypothermia, and 24 h, respectively. These data suggest that the cytokine milieu changes during heat strain recovery with similarities between findings in mice and those described for human heatstroke, supporting the application of our model to the study of cytokine responses in vivo.
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PMID:Time course of cytokine, corticosterone, and tissue injury responses in mice during heat strain recovery. 1623 8

The objective of this study was to investigate energy metabolism of the gut and liver as well as serum inflammatory cytokines following exploratory laparotomy at moderate hypothermia. Two groups of rats were studied, (n=6-8/group); laparotomy at normothermia for 120 min and laparotomy at hypothermia (32-33 degrees C) for 120 min. Study 1: Intestinal glucose, succinate, lactate, phosphocreatine, and ATP as well as hepatic glucose, succinate, lactate, and ATP were measured in terms of micromole per gram using magnetic resonance spectroscopy. Study 2: Serum levels of TNF-alpha, IL-1beta, LPS-inducible chemokine (LIX), and sICAM-1 were measured by ELISA. Histology of the gut and liver were interpreted. Data are expressed as mean and SEM. In Study 1, laparotomy at hypothermia caused an increase in intestinal glucose levels (0.78+/-0.03 vs. 1.29+/-0.11, P=0.0012) with a decrease in hepatic lactate levels (0.82+/-0.04 vs. 0.44+/-0.06, P<0.001). There were no differences in the other metabolites between the two groups. In Study 2, there were no differences in serum TNF-alpha, IL-1beta, LIX, or sICAM-1 between the two groups. Histological features of the gut and liver among groups were comparable. In conclusion, the intestine and liver react to hypothermia differently. However, levels of high-energy phosphates in both organs are not affected by hypothermia suggesting adequate energy for the organs. It is unlikely that hypothermia induces either systemic inflammatory response or hypoxic damage to the intestine and liver in this model.
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PMID:The effects of moderate hypothermia on energy metabolism and serum inflammatory markers during laparotomy. 1632 33

Vasodilatory prostanoids, such as prostacyclin and PGE2, and pro-inflammatory cytokines are known to play a central role in the pathogenesis of endotoxemia. This study was undertaken to elucidate whether indomethacin (INDO), a non-selective COX inhibitor, has protective effects against the cardiovascular alterations that occur during endotoxemia. Sprague-Dawley rats were injected intraperitoneally with 15 mg/kg lipopolysaccharide (LPS). LPS injection led to a prominent decrease in cardiac left ventricular end diastolic area (LVEDA) and increased LV fractional shortening (FS), as measured by echocardigraphy. LPS also led to a significant increase in plasma and myocardial TNF-alpha and IL-1beta levels, and elevated plasma and hypothalamic levels of PGE2. Neither the decrease in LVEDA and the increase in FS, nor the elevation in plasma and myocardial cytokine levels were altered by INDO (10 mg/kg). On the other hand, pretreatment with INDO significantly reduced the elevation in PGE2 and the hypothermia induced by LPS. Taken together, this study demonstrates that solely inhibiting the production of PGE2 is not sufficient to reduce the cardiovascular alteration seen in endotoxemia.
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PMID:Inhibition of prostaglandins does not reduce the cardiovascular changes during endotoxemia in rats. 1634 78

Hypothermia is often associated with compromised host defenses and infection. Deteriorations of immune functions related to hypothermia have been investigated, but the involvement of cytokines in host defense mechanisms and in infection remains unclear. We have previously shown that mild hypothermia modifies cytokine production by peripheral blood mononuclear cells. In this study, the effects of hypothermia on the monocytic production of several cytokines and nitric oxide (NO) were determined. Monocytes obtained from 10 healthy humans were cultured with lipopolysaccharide (LPS) under hypothermic (33 degrees C) or normothermic (37 degrees C) conditions for 48 hours. We performed flow cytometric analysis for simultaneous measurement of interleukin (IL)-8, IL-1beta, IL-6, IL-10, IL-12p70, and tumor necrosis factor (TNF)-alpha in culture supernatants. NO production was quantified as accumulation of nitrite in the medium by a colorimetric assay. Compared with normothermia, mild hypothermia raised the levels of IL-1beta, IL-6, IL-12p70, and TNF-alpha produced by monocytes stimulated with LPS. On calculating the ratios of these elevated cytokines to IL-10, however, only IL-12p70/IL-10 and TNF-alpha/IL-10 ratios were significantly elevated under hypothermic conditions. In contrast, hypothermia did not affect NO production. This study demonstrates that mild hypothermia affects the balance of cytokines produced by monocytes, leading to a pro-inflammatory state. Specifically, monocytic IL-12 and TNF-alpha appear to be involved in the immune alterations observed in mild hypothermia. However, the clinical significance of these phenomena remains to be clarified.
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PMID:Mild hypothermia promotes pro-inflammatory cytokine production in monocytes. 1636 38

Mild hypothermia shows protective effects on patients with brain damage and cardiac arrest. To elucidate the molecular mechanisms underlying these effects, we analyzed the effects of low culture temperature (32 degrees C) and cold-inducible RNA-binding protein (Cirp) expression on apoptosis in vitro. In BALB/3T3 cells treated with tumor necrosis factor (TNF)-alpha and cycloheximide, the down-shift in temperature from 37 degrees C to 32 degrees C increased the expression of Cirp and suppressed the apoptosis. Activation of caspase-8 was suppressed, and the level of phosphorylated extracellular signal-regulated kinase (ERK) was increased. Transduction of Cirp into the Cirp-deficient mouse fibroblasts increased the level of phosphorylated ERK and suppressed the TNF-alpha-induced apoptosis both at 37 degrees C and 32 degrees C. The ERK-specific inhibitor PD98059 decreased the cytoprotective effect of Cirp as well as that of low culture temperature. These data suggest that mild hypothermia protects cells from TNF-alpha-induced apoptosis, at least partly, via induction of Cirp, and that Cirp protects cells by activating the ERK pathway.
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PMID:Cirp protects against tumor necrosis factor-alpha-induced apoptosis via activation of extracellular signal-regulated kinase. 1656 52

We explored the role of the transcription factor c-Fos in lipopolysaccharide (LPS)-induced cytokine response using mice lacking c-Fos (Fos-/- mice). Compared with wild-type controls, Fos-/- macrophages and mice showed significantly enhanced production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12 p40, but reduced production of the anti-inflammatory cytokine IL-10. Bandshift analysis revealed that LPS-induced NF-kappaB binding activity to a functional site in the TNF-alpha promoter was significantly higher in Fos-/- than in wild-type macrophages. Using telemetry, we monitored body temperature and heart rate after LPS injection and found that Fos-/- mice undergo more severe hypothermia and bradycardia than wild-type mice. Such shock responses in Fos-/- mice were significantly reversed by neutralizing TNF-alpha. These data reveal a novel in vivo role for c-Fos as an anti-inflammatory transcription factor acting through suppression of NF-kappaB activity.
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PMID:c-Fos suppresses systemic inflammatory response to endotoxin. 1656 82


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