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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endotoxic reactions induced in mice by recombinant human tumor necrosis factor (TNF) were examined. Mice showed a dose-dependent hypothermia after intravenous TNF injection which was similar to a reaction to lipopolysaccharide injection. Plasma glucose levels were decreased, and plasma lactate levels were increased. Blood hematocrit levels were increased after TNF injection. No interleukin-1 activity was detected in the plasma of TNF-treated animals. The number of leukocytes was reduced 30 min after TNF injection and returned to normal within 24 h. Thus, the data demonstrate that the pathophysiological effects induced by TNF were similar to the effects induced by bacterial endotoxin. Since lipopolysaccharide is a very potent agent for eliciting TNF release from activated macrophages, these results suggest that TNF could act as an endogenous mediator of endotoxin effects.
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PMID:Tumor necrosis factor mediates endotoxic effects in mice. 359 5

Antitumor effects of i.v. injected human recombinant tumor necrosis factor (rTNF) against solid Meth A tumors in mice appeared to be critically dependent on the dose and were limited by its toxicity. Extensive necrosis and complete cures were only induced by doses having untoward effects, such as diarrhea, hypothermia, ruffled fur, and lethargy. Murine tumor necrosis serum (TNS, 0.5 ml) had about the same antitumor potential and induced all side effects except diarrhea. More extensive necrosis and approximate doubling of the incidence of complete regression in the absence of gross side effects were observed upon administration of a low dose of rTNF combined with detoxified endotoxin, nontoxic poly A:U, or submicrogram doses of toxic endotoxin. The separate constituents had little antitumor effects, if any at all. Increasing the dose of toxic endotoxin resulted in a further potentiation of necrosis, overt toxicity, but no cures. Muramyl dipeptide and interferon alpha/beta did not potentiate effects of rTNF. In vitro growth of Meth A cells was not inhibited by toxic endotoxin, rTNF or the combination, although TNS was highly inhibitory. Data show that therapeutic effects of rTNF and its synergy with endotoxin are not due to direct effects on the tumor cells and that the extent of prompt in vivo tumor necrosis does not predict the course of tumor growth. Therapeutic effects of both TNS and toxic endotoxin probably involve a synergy between low levels of TNF and other factors/effects induced by endotoxin. Detoxified endotoxin and poly A:U probably induce the latter effects and little or no TNF, so explaining the absence of side effects, their weak antitumor potential, and their powerful synergistic action with rTNF. A role for interferon alpha/beta as an induced synergistic factor is not likely. Muramyl dipeptide and TNF might share properties needed for synergy with endotoxins.
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PMID:Synergistic action of human recombinant tumor necrosis factor with endotoxins or nontoxic poly A:U against solid Meth A tumors in mice. 382 51

Repetitive administration of low doses of tumor necrosis factor (TNF) induces a selective tolerance to some, but not all, of its effects. The aim of the present study was to define the pathways involved in tolerance. We observed that the induction of tolerance is mediated by TNF-R55 triggering. TNF-R75 triggering or the addition of sensitizers can interfere with this induction but does not break an acquired tolerance, inasmuch as tolerant animals were also tolerant to otherwise lethal challenges with the combination of human TNF and the sensitizers interleukin-1 and RU-38486. We further defined the selectivity of the tolerance by examining changes in quantitative parameters such as interleukin-6 induction, hypothermia, and hemoconcentration. The differences between tolerant and nontolerant animals mimicked those observed after administration of human TNF vs. murine TNF and were to be found in the duration rather than in the amplitude of the induced changes. We conclude that tolerance selectively blocks the TNF-R75-mediated pathway, especially the part mimicked by interleukin-1 and RU-38486; this pathway normally leads to a state of unresponsiveness to glucocorticoids.
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PMID:Mechanism of tolerance to tumor necrosis factor: receptor-specific pathway and selectivity. 765 62

The present study was designed to investigate the role of macrophages and circulating tumor necrosis factor-alpha (TNF-alpha) in the endotoxin-induced hypothermic responses in rats. Intravenous as well as intraperitoneal administration of endotoxin to male Wistar rats (0.5 mg/kg) led to increased plasma TNF-alpha concentrations and a transient hypothermia, which reached its nadir after 90 min. The hypothermia and plasma TNF-alpha responses to endotoxin were abolished after elimination of peripheral macrophages. Seven days after the first challenge, tolerance of the hypothermic response was found if the same dose was administered intraperitoneally but not if it was administered intravenously. Tolerance of the TNF-alpha response was induced irrespective of the route of endotoxin administration. We hypothesize that, after intravenous administration of endotoxin, macrophage-dependent and -independent mechanisms are activated, whereas the hypothermic response to intraperitoneal endotoxin involves primarily macrophage-dependent mechanisms. These mechanisms may relate to the prime targets reached by endotoxin, such as macrophages and endothelial cells. Because the development of tolerance of the hypothermic response is dependent on the route of endotoxin administration, whereas that of the plasma TNF-alpha response is not, we conclude that circulating TNF-alpha is not the macrophage-derived cryogenic signal that triggers the hypothermic response.
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PMID:Circulating tumor necrosis factor-alpha does not mediate endotoxin-induced hypothermia in rats. 773 9

The proinflammatory cytokines have been implicated in mediating myocardial dysfunction associated with myocardial infarction, severe congestive heart failure, and sepsis. We tested the hypothesis that cytokine levels are elevated after uncomplicated coronary artery bypass grafting and associated with episodes of postoperative myocardial ischemia and dysfunction. Coronary artery bypass grafting was performed under general anesthesia with moderate systemic hypothermia and cold-blood potassium cardioplegic solution. Tumor necrosis factor-alpha and interleukin-6 levels were determined by bioassays, and interleukin-8 levels were measured by a sandwich enzyme-linked immunosorbent assay. Myocardial function and ischemic episodes were assessed by intraoperative transesophageal echocardiography and perioperative 12-channel Holter monitoring. A total of 22 patients were studied, with no deaths or complications. Arterial tumor necrosis factor-alpha rose in a bimodal distribution, peaking at 2 and 18 to 24 hours after the operation (at 20.2 +/- 6.4 pg/ml, [mean +/- standard error of the mean]) and 5.8 +/- 1.6 pg/ml, respectively; before cardiopulmonary bypass: 0.90 +/- 0.20 pg/ml, p < 0.001 for both peaks) then progressively declined to levels before bypass. Arterial interleukin-6 was maximally elevated immediately on termination of cardiopulmonary bypass and peaked again 12 to 18 hours after cardiopulmonary bypass (at 7520 +/- 2439 pg/ml and 6216 +/- 1928 pg/ml, respectively; before bypass: 746 +/- 187 pg/ml, p < 0.0001 for both peaks). Arterial interleukin-8 levels were more variable but followed a similar pattern, peaking in the early period after cardiopulmonary bypass and again at 16 to 18 hours after the operation (at 4110 +/- 1403 pg/ml and 1760 +/- 1145 pg/ml, respectively; before bypass: 461 +/- 158, p < 0.05 for both peaks). By multivariate analysis, the aortic crossclamp time was independently predictive of postoperative cytokine levels. Left ventricular wall motion abnormalities were associated with both interleukin-6 and interleukin-8 levels, worsening scores being associated with increasing levels (for interleukin-6, p = 0.003; for interleukin-8, p = 0.05). Postoperative myocardial ischemic episodes were associated with interleukin-6 levels, six of seven (85%) patients with episodes of myocardial ischemia after a peak in interleukin-6 concentrations (p < 0.01). We conclude that proinflammatory cytokines are elevated after uncomplicated coronary revascularization and may contribute to postoperative myocardial ischemia and segmental wall motion abnormalities.
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PMID:Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. 793 95

Previously, we have reported that intravenous administration of bacterial endotoxin (lipopolysaccharide, LPS) in rats kept at a subthermoneutral ambient temperature of 24 degrees C results in a fall in colonic temperature that involved the release of antipyretic products by peripheral macrophages. Here, we demonstrate that treatment of rats with a biologically active antiserum to tumor necrosis factor (TNF) markedly attenuates the hypothermia in response to administration of LPS (0.5 mg/kg). Moreover, this hypothermia was prevented by central injection of a selective antagonist of V1 vasopressin receptors, dPTyr(Me) arginine vasopressin (AVP; 2 micrograms icv). AVP is thought to act as an antipyretic in the ventral septal area (VSA) of the brain. Because the AVP content of this area has been shown to be eliminated after long-term castration, we have tested the hypothesis that castration would attenuate the hypothermia in response to administration of LPS. Castrated rats displayed a markedly less hypothermic response than age-matched controls in response to administration of LPS. We conclude that hypothermia in response to intravenous injection of LPS involves the release of TNF from peripheral macrophages. Moreover, our results are consistent with the possibility that androgen-dependent vasopressinergic neurons in the VSA are mediating the hypothermia in response to intravenous administration of LPS.
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PMID:Hypothermia to endotoxin involves the cytokine tumor necrosis factor and the neuropeptide vasopressin in rats. 830 60

Because of its ability to efficiently inhibit in vitro cytokine production by activated macrophages, we hypothesized that interleukin (IL) 10 might be of particular interest in preventing endotoxin-induced toxicity. We therefore examined the effects of IL-10 administration before lipopolysaccharide (LPS) challenge in mice. A marked reduction in the amounts of LPS-induced tumor necrosis factor (TNF) release in the circulation was observed after IL-10 pretreatment at doses at low as 10 U. IL-10 also efficiently prevented the hypothermia generated by the injection of 100 micrograms LPS. Finally, pretreatment with a single injection of 1,000 U IL-10 completely prevented the mortality consecutive to the challenge with 500 micrograms LPS, a dose that was lethal in 50% of the control mice. We conclude that IL-10 inhibits in vivo TNF secretion and protects against the lethality of endotoxin in a murine model of septic shock.
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PMID:Interleukin 10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia. 842 24

Lethal circulatory shock during microbial sepsis is thought to be initiated by early molecular events, including production of tumor necrosis factor (TNF) and cytokine-mediated upregulation of neutrophil (PMN) function, irrespective of the causative organism. The phosphodiesterase inhibitor pentoxifylline (PTX) inhibits TNF gene transcription and modulates PMN function, and has been shown to improve outcome in experimental sepsis. We hypothesized that PTX would attenuate gram-negative and fungal septic shock by different mechanisms: reduced TNF production in Escherichia coli (EC) sepsis vs. enhanced PMN-mediated defense during Candida albicans (CA) fungemia. Conscious chronically catheterized rats received PTX (25 mg/kg, i.v.) before i.v. challenge with 10(10) viable EC (serotype 055:B5), 10(9) viable serotype A yeast-phase CA (each the LD100 in < 24 hr in naive rats), or normal sterile saline (NSS), and then PTX posttreatment (6.5 mg/hr x 4.5 hr). Treatment controls received NSS before and after challenge. Serum TNF peaked 1.5 hr after EC infection in NSS-treated animals (1654 +/- 390 U/ml, mean +/- SE), and was significantly reduced by PTX (120 +/- 32 U/ml, P < 0.01), but PTX did not improve 24 hr survival. PTX also aggravated systemic hypotension after EC, and did not modify neutropenia, thrombocytopenia, or microvascular permeability assessed by organ wet/dry weight (W/D) ratios. Peak serum TNF in CA + NSS animals (130 +/- 45 U/ml) was delayed 8 hr compared to EC animals, and were not reduced by PTX (67 +/- 25 U/ml, P = NS). Moreover, PTX did not alter CA-induced mortality, hypothermia, hypotension, neutropenia, increased lung W/D, or interstitial and alveolar hemorrhage. We conclude that PTX-induced suppression of endogenous TNF production does not prevent gram-negative shock in this model, possibly due to impaired TNF-mediated antibacterial host defense. Since fungal septic shock with acute disseminated candidiasis evolves prior to significant increases in circulating TNF, PTX also appears ineffective in its treatment.
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PMID:Effects of pentoxifylline on tumor necrosis factor production and survival during lethal E. coli sepsis vs. disseminated candidiasis with fungal septic shock. 848 22

Cyclophosphamide-induced neutropenia exacerbates septic shock and multiple organ injury in conscious rats during Escherichia coli (EC) bacteremia despite antibiotics and fluid administration. We hypothesized that such shock and inflammatory organ injury would be mitigated by rBPI23's microbicidal activity and/or binding of EC endotoxins. Four days after 100 mg cyclophosphamide/kg, catheterized rats with < 300 PMNs/microL were pretreated with rBPI23 or the irrelevant 22 kDa protein thaumatin [3.3-6.6 mg/kg, i.v. in 0.9% NaCl (NS)] 5 min before graded i.v. infection with 5 x 10(9) or 1 x 10(10) cfu of EC serotype 055:B5 ending at t = 0. Posttreatment with each protein continued (3.3-6.6 mg/kg in 1 mL NS/h) through 8 h, in addition to penicillin plus amikacin sulfate at t = 1.5 and 8 h. Arterial samples were obtained before pretreatment and at t = 1.5, 4.5, 8, and 24 h when animals were necropsied. One of eight thaumatin + 5 x 10(9) EC rats and none of six thaumatin + 10(10) EC rats survived 24 h. In contrast, rBPI23 significantly reduced mortality after either inoculum, improved bacterial clearance, and led to renormalization of early EC-induced hypotension, hypothermia, tachypnea, hyperoxemia, and hypocarbia. Compared with thaumatin, however, rBPI23 did not reduce circulating endotoxin or bioactive and antigenic tumor necrosis factor-alpha. Sepsis-induced severe neutropenia (< 50 PMNs/microL) evident in all EC rats by t = 1.5 h was reversed with rBPI23 by t = 8 h, but thrombocytopenia (< 5 x 10(4) platelets/microL) evident in all groups by t = 4.5 h was not altered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The recombinant 23-kDa N-terminal fragment of bactericidal/permeability-increasing protein (rBPI23) decreases Escherichia coli-induced mortality and organ injury during immunosuppression-related neutropenia. 856 60

To evaluate cytokine balance related to cardiopulmonary bypass, we prospectively investigated 11 infants undergoing cardiac operations for congenital heart disease. Proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-8) and the antiinflammatory cytokine interleukin-10 were measured at multiple time points before, during, and after bypass. Tumor necrosis factor-alpha and interleukin-8 values were within normal range before the operation. These values increased significantly during bypass, reaching their peaks after protamine administration (tumor necrosis factor-alpha, 133.6 +/- 124.9 pg/ml; mean +/- standard deviation; p<0.005) and 2 hours after termination of the procedure (interleukin-8, 92.1 +/- 44.1 pg/ml; p < 0.01). Tumor necrosis factor-alpha and interleukin-8 equaled normal prebypass values from the first postoperative day on. Interleukin-10 levels were within normal range before the operation and were already significantly increased 10 minutes after initiation of bypass (interleukin 10, 39.4 +/- 34.3 pg/ml; p<0.05). These levels remained elevated throughout the procedure but returned to normal after protamine administration. A second significant release of interleukin-10 occurred from the early postoperative period on, reaching its peak 24 hours after termination of cardiopulmonary bypass (interleukin-10, 351.6 +/- 304.0 pg/ml; p < 0.01). Interleukin-10 values were normal on the second postoperative day in all patients. Interleukin-10 kinetics showed an inverse pattern compared with tumor necrosis factor-alpha and interleukin-8. This difference suggests an interplay between proinflammatory and antiinflammatory cytokines released during and after cardiopulmonary bypass. Interleukin-10 levels measured 4 and 24 hours after bypass strongly correlated with the degree of hypothermia during bypass (Spearman's correlation coefficient, -0.77 [p < 0.01] and -0.89 [p < 0.0005], respectively); these levels did not correlate with duration of bypass and aortic crossclamping, however. This result suggests that besides immunologically mediated production of interleukin-10, hypothermia itself could modulate interleukin-10 production. In conclusion, this study demonstrates interleukin-10 production, in addition to interleukin-8 and tumor necrosis factor-alpha synthesis, in response to cardiopulmonary bypass in infants. Interleukin-10 could play a protective role by down-regulating proinflammatory cytokine release during and after cardiopulmonary bypass.
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PMID:Interleukin-10 release related to cardiopulmonary bypass in infants undergoing cardiac operations. 860 68


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