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)

We analyzed the role of adhesion molecules in the pathogenesis of experimental cerebral malaria (ECM), since tumor necrosis factor (TNF) plays a major role in this condition and has been shown to up-regulate in vitro expression of cell adhesion molecules (CAM), particularly intercellular CAM-1 (ICAM-1). We found increased expression of ICAM-1 on brain endothelial cells from mice with ECM. Treatment with monoclonal antibodies (mAb) directed against leukocyte function-antigen 1 (LFA-1, the ligand of ICAM-1) on days 6, 8 and 10 almost totally prevented ECM, while decreasing blood TNF levels. To exclude the possibility that the effects of anti-LFA-1 mAb resulted from an even partial inhibition of TNF overproduction, mice with signs of imminent death (hypothermia and neurologic defects) were treated with the anti-LFA-1 mAb, with dramatically protective effect. In contrast, injection of anti-ICAM-1 mAb on day 6 caused rapid death, while it was innocuous in normal mice. An mAb directed against complement receptor type 3 (CR3) was ineffective, as were injections of soluble human ICAM-1. These results suggest that adhesion of LFA-1+ cells to endothelial cells, stimulated by TNF to express high levels of ICAM-1, is critical in the pathogenesis of ECM. Emergency therapy at interfering with cytoadherence could be considered in the treatment of cerebral malaria in man, in which high blood TNF levels are also observed.
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PMID:Late administration of monoclonal antibody to leukocyte function-antigen 1 abrogates incipient murine cerebral malaria. 167 17

Pretreatment with pentoxifylline (PTX), a methylxanthine known for its beneficial effects on tissue lesions induced by the injection of endotoxin or recombinant cytokines, was shown to decrease the systemic release of tumor necrosis factor and interleukin 2 occurring after the administration of the anti-CD3 monoclonal antibody 145-2C11 in mice. In parallel, PTX attenuated the hypothermia and the rise in blood urea nitrogen observed in this model. The protective effect of PTX on the toxicity of 145-2C11 was confirmed by the reduction of the mortality among D-galactosamine-sensitized animals. The mitigation by PTX of the release of cytokines did not affect the immunosuppression entailed by 145-2C11 as assessed by the unmodified cytotoxic T lymphocytes (CTL) unresponsiveness against alloantigens measured 48 hr after the injection of the mAb. In vitro experiments on human peripheral blood leukocytes indicated that PTX alone or in synergy with methylprednisolone (m-PDS) also inhibited the release of TNF and IL-2 induced by OKT3. Finally, in a preliminary pilot trial conducted in kidney transplant recipients, we observed that pretreatment with PTX (20 mg/kg i.v.) in addition to m-PDS (2 g i.v.) reduced by half the amount of TNF released in the blood stream after the first injection of OKT3, while no further reduction of the low levels of IL-2 was found.
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PMID:Evidence that pentoxifylline reduces anti-CD3 monoclonal antibody-induced cytokine release syndrome. 183 65

Oral exposure to T-2 Toxin (T-2) in experimental animals results in a syndrome similar to that observed in endotoxemia. Endotoxins are lipopolysaccharide, outer-membrane components of gram-negative bacteria which induce acute, inflammatory responses. In the present study, several aspects of endotoxin pathophysiology were investigated in mice following simultaneous exposure to T-2 and endotoxin, including mortality, hypothermia, tumor necrosis factor-alpha (TNF-alpha) and corticosterone production, and thymic weight. The disposition of endotoxin was also assessed, Acute, simultaneous exposure to T-2 (4 mg/kg, po) and endotoxin (3 micrograms/mouse, ip) resulted in increased mortality, hypothermia, TNF-alpha production, and thymic atrophy compared to treatment with either T-2 of endotoxin alone. Pretreatment of mice with endotoxin, a regime that renders the animals resistant to the effects of endotoxin, reduced many endotoxin effects in animals treated simultaneously with T-2 and endotoxin. Upon further investigation, it was observed that T-2 increased the absorption rate of endotoxin: as the peak height of serum endotoxin increased, the time-to-peak decreased, and the area under the curve was unchanged in animals treated simultaneously with T-2 and endotoxin. It was concluded that increased endotoxin absorption accounted for the increases in mortality, hypothermia, and TNF-alpha associated with T-2 exposure.
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PMID:Increased endotoxin sensitivity following T-2 toxin treatment is associated with increased absorption of endotoxin. 203 49

The purpose of these studies was to test whether pentoxifylline, a drug that can inhibit the production and action of cytokines hypothesized to be endogenous pyrogens (for example, interleukin 1 and tumor necrosis factor [TNF]), is antipyretic. We also tested the effects of pentoxifylline on plasma activities of interleukin 6 (IL 6) and TNF in response to an injection of a fever-inducing dose of lipopolysaccharide (LPS). Our results showed that a high dose of pentoxifylline (200 mg/kg) caused hypothermia in control rats and blocked LPS fever, while a low dose (50 mg/kg) did not have these effects. Injection of the high dose of pentoxifylline in control rats caused a rise in plasma IL 6 but not in plasma TNF. However, the peak levels of plasma IL 6 and TNF activities following an injection of LPS were significantly reduced by pretreatment with pentoxifylline. Overall, the data are consistent with the hypothesis that pentoxifylline is an antipyretic drug, which may act at least in part by inhibiting the secretion of pyrogenic cytokines.
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PMID:The effects of pentoxifylline on lipopolysaccharide (LPS) fever, plasma interleukin 6 (IL 6), and tumor necrosis factor (TNF) in the rat. 210 30

In vivo injection of the hamster anti-murine CD3 monoclonal antibody 145 2C11 into BALB/c mice induces a massive systemic release of several cytokines. Very high circulating levels of tumor necrosis factor are detected both by enzyme-linked immunosorbent assay and L-929 bioassay 90 min following a single injection of 10 micrograms/mouse 145 2C11. Peak circulating levels of exclusively T cell-derived products such as interferon-gamma, interleukin 2 and interleukin 3 are also detected 90 min to 8 h post-injection. Importantly, this cytokine release is transient since none of these cytokines are still present 12 to 24 h post-injection. In parallel to cytokine release, 145 2C11-treated mice (10 micrograms/mouse) exhibit somnolence, hypomotility (quantified by actimetry), hypothermia, diarrhea and piloerection. At this dosage, the physical reaction is not lethal and reverses in all mice by 48 h post-injection. Severe but again reversible anatomopathological changes are also observed: massive cellular depletion, necrosis and edema of lymphoid organs, leakage syndrome and inflammatory cell infiltrates of the lung, cell vacuolization, necrosis and vascular congestion of the liver. All these data are similar to the clinical and immunological manifestations of the OKT3-induced reaction in patients and, thus, provide an invaluable experimental tool to study its mechanisms and explore its prevention.
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PMID:Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: further evidence for transient in vivo T cell activation. 213 57

The possible involvement of tumor necrosis factor-alpha (TNF) in the metabolic disturbances induced by anti-CD3 monoclonal antibodies (mAb) was analyzed in DBA/2 mice injected with 50 micrograms of the anti-murine CD3 mAb 145-2C11. First, we found that 145-2C11 induces a profound hypothermia maximal between 3 h and 6 h after the injection (at 3 h: -3.0 +/- 0.1 degrees C) as well as hypoglycemia (blood glucose levels at 6 h and 24 h: 76 +/- 13 mg/100 ml and 92 +/- 22 mg/100 ml, respectively, p less than 0.001 as compared with control values). These metabolic changes are preceded by the release of TNF into the circulation (peak serum TNF levels at 2 h: 50 +/- 23 pg/ml, p less than 0.01 as compared with controls). The release of TNF induced by 145-2C11 depends on the effect of the mAb on T cells as it is not observed in athymic nude mice while lipopolysaccharide-resistant C3H/HeJ mice also display a significant rise in serum TNF (peak levels at 2 h: 59 +/- 44 pg/ml). Pretreatment of DBA/2 mice with 12 mg of rabbit anti-murine TNF antibodies completely prevents the hypothermia while the hypoglycemia is significantly attenuated. Finally, F(ab')2 fragments of 145-2C11 induce only a transient hypoglycemia (blood glucose levels at 6 h: 109 +/- 14, p less than 0.001 as compared with controls) but neither hypothermia nor significant TNF release. We conclude that TNF is a major mediator of the acute metabolic changes induced by the intact form of 145-2C11.
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PMID:Hypothermia and hypoglycemia induced by anti-CD3 monoclonal antibody in mice: role of tumor necrosis factor. 213 64

An increased sensitivity of adrenalectomized (Adex) rats to intravenous (IV) injection of recombinant human tumor necrosis factor (rHuTNF) was manifested by a marked increase in the rate of mortality. The rats that died exhibited severe hypoglycemia and hypothermia. Administration of 2.5 or 10 micrograms/100 g body weight (3% or 12%) of the lethal dose in sham-operated rats (90 micrograms/100 g body weight) rHuTNF caused a mortality rate of 50% or 100%, respectively, within 4 hours of its injection. Pre-administration of dexamethasone or intermittent glucose infusion protected the animals from the lethal effect of rHuTNF. Indomethacin did not change the mortality rate in rHuTNF-treated Adex rats, but prevented it in sham-operated rats. The rats that died exhibited a marked decrease in body temperature, but only Adex rats developed hypoglycemia after low doses of TNF. Pretreatment with dexamethasone prevented the hypothermia in both Adex and sham-operated rats, while indomethacin was effective only in sham-operated rats and did not prevent the hypothermia or the hypoglycemia in Adex rats. In the surviving rHuTNF-treated Adex rats, a rapid increase in body temperature occurred, blood glucose decreased to 30 mg/dL, serum insulin concentration decreased to 6 microU/mL, liver glycogen content was reduced by 98%, and a significant reduction in liver phosphoeonolpyruvate carboxykinase (PEPCK) and liver microsomal glucose-6-phosphatase activities was observed. Repeated administration of glucose IV to rHuTNF-treated Adex rats caused an increase in blood glucose and insulin concentrations, and some repletion in liver glycogen content. Injection of rHuTNF, 2.5 to 10 micrograms/100 g body weight, to sham-operated rats caused a significant but slower increase in body temperature.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lethal hypoglycemia and hypothermia induced by administration of low doses of tumor necrosis factor to adrenalectomized rats. 215 69

The ability of Escherichia coli-derived lipopolysaccharide (LPS), recombinant (r) interleukin 1-beta (rIL-1 beta), and r murine tumor necrosis factor-alpha (rMuTNF-alpha) to induce interleukin 6 (IL-6) production in vivo was investigated. Peak serum IL-6 concentration was attained after 2 hr of LPS injection into mice. The coinjection of antiserum against rMuTNF-alpha with LPS resulted in a reduction of the induced serum IL-6 level, indicating the involvement of endogenous TNF-alpha in LPS induction of IL-6. Recombinant IL-1 beta and rMuTNF-alpha injected directly caused the production of substantial amounts of IL-6 within 30 min. The injection of a combination of rIL-1 beta and rTNF-alpha induced a significantly greater level of IL-6 than either agent alone. The greater level of serum IL-6 was associated with hypothermia and an increased lethality among mice injected with both cytokines. These data demonstrate the abilities of IL-1 beta and TNF-alpha to induce IL-6 production in vivo and indicate that LPS induction of IL-6 may be mediated, at least partially, through TNF-alpha action. The data describe a new in vivo biologic activity shared between IL-1 beta and TNF-alpha and suggest that IL-6 may be an important effector in the manifestation of TNF-alpha and IL-1 beta actions in vivo.
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PMID:Endotoxin, tumor necrosis factor-alpha and interleukin 1 induce interleukin 6 production in vivo. 280 53

An early-phase tolerance to toxic doses of lipopolysaccharide (LPS) can be induced in mice by prior administration of sublethal doses of LPS or lipid A. These tolerant mice exhibit no hypothermia on subsequent administration of LPS and can survive a challenge dose of LPS that would normally be lethal. Peritoneal exudate cells of LPS-tolerant mice synthesized significantly reduced amounts of prostaglandins and of procoagulant activity (PCA) and tumor necrosis factor (TNF) when stimulated with LPS in vitro (compared to macrophages of control animals). Tolerance induction with lipid A was somewhat less effective. A regulatory mechanism of E-series prostaglandins (PGE) might be involved in the induction of hyporesponsiveness in macrophages of tolerant mice, as the LPS-stimulated TNF release could be inhibited in a dose dependent manner by preincubation with PGE1. Since PCA and TNF are mediators that are proposed to play a very important role in the pathophysiology of septic and endotoxic shock, a reduction in the release of these mediators may be partially responsible for early-phase tolerance to LPS.
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PMID:Reduced release of TNF and PCA from macrophages of tolerant mice. 319 64

Endotoxin-induced tumor necrosis has been shown to be mediated by a factor termed tumor necrosis factor (TNF). The biochemical nature, source, and mode of induction of TNF have been clarified. TNF is a mediator of activated macrophages that is released into the supernatant by these cells after their stimulation with endotoxin. A number of biologic functions of TNF other than its tumoricidal activity have been demonstrated. In vivo, TNF induces reactions similar to those induced by endotoxin. Hypothermia, elevated hematocrit and plasma lactate levels, and reduced plasma glucose levels have been measured in mice injected with TNF. These reactions typically occur soon after endotoxin injection and are induced with purified recombinant TNF in mice that exhibit a low response to endotoxin. No TNF-induced production of interleukin 1 (which can induce similar effects) was detected in macrophage/monocyte cultures. Therefore, TNF appears to mediate endotoxin effects directly.
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PMID:Tumor necrosis factor: a cytokine involved in toxic effects of endotoxin. 350 Apr 95


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