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

Double-stranded (ds)RNA is made as a by-product of viral replication. Synthetic dsRNA induces virtually all of the same systemic symptoms as acute viral infections, such as fever and malaise. In order to develop a model of respiratory viral infections (such as influenza) suitable for use in gene knockout mice (where the deleted gene may affect viral replication), we examined C57BL/6 mouse body temperature and locomotor activity responses to the synthetic dsRNA polyriboinosinic.polyribocytidylic acid (poly[rI.rC]) introduced via the intratracheal (IT) route. We compared the IT poly[rI.rC] responses to the well-characterized intraperitoneal (IP) poly[rI.rC] responses. IT poly[rI.rC] failed to induce an acute phase response (APR) in mice, in contrast to IP poly[rI.rC]. However, addition of interferon (IFN)gamma to the IT poly[rI.rC] inoculum induced sustained hypothermia and suppressed locomotor activity responses with similar kinetics to those responses seen in acute mouse influenza. We further examined cytokine, antiviral, muscarinic M2 receptor and inducible nitric oxide synthase gene expression at 5 hr in the lungs of IT challenged mice. These studies suggested that priming the lung with IFNgamma could enhance proinflammatory (IL1beta, IL6, TNFalpha) cytokine gene expression and suppress interferon gene expression compared to IT poly[rI.rC] alone. No differences were detected for the other genes examined. While further molecular characterization of the model is required, we demonstrate that IT challenge with combined poly[rI.rC] and IFNgamma closely simulates the APR to an acute respiratory virus, and may serve as a suitable model for analyzing the molecular basis of the viral APR in gene knockout mice.
 ...
PMID:Intratracheal double-stranded RNA plus interferon-gamma: a model for analysis of the acute phase response to respiratory viral infections. 1501 Feb 66

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.
 ...
PMID:Hypothermia prolongs activation of NF-kappaB and augments generation of inflammatory cytokines. 1507 Aug 15

Infectious challenge triggers a broad array of coordinated changes within the host organism, including alterations in sleep-wake behavior and body temperature. Pro-inflammatory cytokines orchestrate many of the behavioral, metabolic, and endocrine responses to immune challenge. Although interleukin (IL)-6 mediates several aspects of sickness behavior, a role for this cytokine as a mediator of alterations in sleep in response to immune challenge has not been established. We evaluated sleep-wake behavior and core body temperature of IL-6-deficient (IL-6 KO; B6.129S6-Il6tm1Kopf) mice and C57BL/6J control mice after intraperitoneal (IP) administration of 10 microg lipopolysaccharide (LPS). Because feedback mechanisms that regulate responses to immune challenge exhibit circadian rhythms, we evaluated responses to LPS administered at the beginning of both the light and dark portions of the light:dark cycle. LPS-induced increases in non-rapid eye movements sleep (NREMS) of both mouse strains, but this increase was less pronounced in IL-6 KO mice than in C57BL/6J mice. Strain differences in LPS-induced increases in NREMS were greatest after light-onset administration. During the 12 h light period, NREMS of C57BL/6J mice increased from 53.0+/-1.7% of recording time after vehicle to 65.4+/-1.4% of recording time after LPS. During this same time period, NREMS of IL-6 KO mice increased from 50.5+/-1.8% after vehicle to only 52.4+/-1.8% of recording time after LPS. REMS of both mouse strains was suppressed to the same extent after LPS, irrespective of timing of administration. LPS-induced fever in C57BL/6J mice, with peak magnitude of 1.4+/-0.3 degrees C and 1.8+/-0.2 degrees C after dark onset and light onset administration, respectively. In contrast, this dose of LPS-induced profound hypothermia in IL-6 KO mice, with nadirs of hypothermia reaching 4.9+/-1.0 degrees C after injection at dark onset and 2.2+/-0.5 degrees C after administration at light onset. These results indicate that IL-6 mediates some of the effects of LPS on NREMS and body temperature of mice, and that the magnitude and duration of these effects differ as a function of the time at which the challenge is given.
 ...
PMID:Diurnal variation of lipopolysaccharide-induced alterations in sleep and body temperature of interleukin-6-deficient mice. 1558 37

Staphylococcal enterotoxins (SEs) belong to a large group of bacterial exotoxins that cause severe immunopathologies, especially when delivered as an aerosol. SEs elicit the release of lethal amounts of cytokines by binding to major histocompatibility complex (MHC) class II and cross-linking susceptible T-cell receptors. Efforts to develop effective therapeutic strategies to protect against SEs delivered as an aerosol have been hampered by the lack of small animal models that consistently emulate human responses to these toxins. Here, we report that human leukocyte antigen-DQ8 (HLA-DQ8) transgenic (Tg) mice, but not littermate controls, succumbed to lethal shock induced by SEB aerosols without potentiation. Substantial amounts of perivascular edema and inflammatory infiltrates were noted in the lungs of Tg mice, similar to the pathology observed in nonhuman primates exposed by aerosol to SEB. Furthermore, the observed pathologies and lethal shock correlated with an upsurge in proinflammatory cytokine mRNA gene expression in the lungs and spleens, as well as with marked increases in the levels of proinflammatory circulating cytokines in the Tg mice. Unlike the case for littermate controls, telemetric evaluation showed significant hypothermia in Tg mice exposed to lethal doses of SEB. Taken together, these results show that this murine model will allow for the examination of therapeutics and vaccines developed specifically against SEB aerosol exposure and possibly other bacterial superantigens in the context of human MHC class II receptors.
 ...
PMID:Human leukocyte antigen-DQ8 transgenic mice: a model to examine the toxicity of aerosolized staphylococcal enterotoxin B. 1578 91

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.
 ...
PMID:Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se-- not by lipoprotein contaminants. 1586 Jun 47

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.
 ...
PMID:Hepatic over-expression of TGF-beta1 promotes LPS-induced inflammatory cytokine secretion by liver cells and endotoxemic shock. 1605 5

Our previous studies showed that beta(2)-microglobulin knockout mice treated with anti-asialoGM1 (beta2MKO/alphaAsGM1 mice) are resistant to injury caused by cecal ligation and puncture (CLP). However, CLP-induced injury is complex. Potential mechanisms of injury include systemic infection, cecal ischemia, and translocation of bacterial toxins such as endotoxin and superantigens. Currently, it is unclear which of these mechanisms of injury contributes to mortality in wild-type mice and whether beta2MKO/alphaAsGM1 mice are resistant to any particular mechanisms of injury. In the present study, we hypothesized that systemic infection is the major cause of injury after CLP in wild-type mice and that beta2MKO/alphaAsGM1 mice are resistant to infection-induced injury. To test this hypothesis, wild-type and beta2MKO/alphaAsGM1 mice were treated with the broad-spectrum antibiotic imipenem immediately after CLP to decrease the impact of systemic infection in our model. Treatment of wild-type and beta2MKO/alphaAsGM1 mice with imipenem decreased bacterial counts by at least two orders of magnitude. However, all wild-type mice, whether treated with saline or imipenem, died by 42 h after CLP and had significant hypothermia, metabolic acidosis, and high plasma concentrations of the cytokines interleukin-6, macrophage inflammatory protein-2, and keratinocyte-derived chemokine. beta2MKO/alphaAsGM1 mice showed 40% long-term survival, which was increased to 90% by imipenem treatment. beta2MKO/alphaAsGM1 mice had less hypothermia, decreased metabolic acidosis, and lower cytokine concentrations at 18 h after CLP compared with wild-type mice. These results suggest that infection is not the major cause of mortality for wild-type mice in our model of CLP. Other mechanisms of injury such as cecal ischemia or translocation of microbial toxins may be more important. beta2MKO/alphaAsGM1 mice appear resistant to these early, non-infection-related causes of CLP-induced injury but showed delayed mortality associated with bacterial dissemination, which was ablated by treatment with imipenem.
 ...
PMID:Differential effect of imipenem treatment on injury caused by cecal ligation and puncture in wild-type and NK cell-deficient beta(2)-microgloblin knockout mice. 1616 41

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.
 ...
PMID:Time course of cytokine, corticosterone, and tissue injury responses in mice during heat strain recovery. 1623 8

CD8 knockout mice depleted of natural killer (NK) cells by treatment with anti-asialoGM1 (CD8KO/alphaAsGM1 mice) are resistant to injury caused by cecal ligation and puncture (CLP). However, CLP-induced injury is complex. Potential sources of injury include bacterial dissemination, cecal ischemia, and translocation of bacterial toxins. We treated wild-type and CD8KO/alphaAsGM1 mice with imipenem after CLP to decrease bacterial dissemination. Additional mice were subjected to cecal ligation without puncture of the cecal wall or cecal ligation and removal of cecal contents. Imipenem treatment decreased bacterial counts by at least two orders of magnitude. However, all wild-type mice, whether treated with saline or imipenem, died by 42 h after CLP and exhibited significant hypothermia, metabolic acidosis, and high plasma cytokine concentrations. Wild-type mice subjected to cecal ligation without puncture also died, despite very low bacterial counts in blood, but wild-type mice subjected to cecal ligation and washout of cecal contents survived. In CD8KO/alphaAsGM1 mice subjected to CLP, imipenem treatment increased survival from 50% to 100%. After cecal ligation without puncture, long-term survival was 80-90% in CD8KO/alphaAsGM1 mice. Hypothermia, metabolic acidosis, and cytokine production were attenuated in CD8KO/alphaAsGM1 mice compared with wild-type controls. These results indicate that bacterial dissemination is not a major source of injury in wild-type mice after CLP, but the presence of gut flora in the cecal lumen is required for induction of systemic inflammation after cecal injury. CD8KO/alphaAsGM1 mice are resistant to the systemic manifestations of cecal injury.
 ...
PMID:Differential effect of imipenem treatment on wild-type and NK cell-deficient CD8 knockout mice during acute intra-abdominal injury. 1626 70

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.
 ...
PMID:Inhibition of prostaglandins does not reduce the cardiovascular changes during endotoxemia in rats. 1634 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>