Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The contribution of granulocyte-macrophage CSF (GM-CSF) to endotoxin-mediated septic shock has been assessed by treating GM-CSF-deficient mice with LPS. Hypothermia and loss in body weight were markedly attenuated in LPS-treated GM-CSF-deficient mice compared with similarly treated control mice; moreover, the levels of circulating IFN-gamma, IL-1alpha, and IL-6 were lower in LPS-treated GM-CSF-deficient mice than LPS-treated control mice. Intriguingly, the peak levels of TNF-alpha in response to LPS treatment were the same in the serum of GM-CSF-deficient mice and control mice, although in GM-CSF-deficient mice, TNF-alpha persisted longer. Activation of macrophages by LPS, resulting in expression of cytokines including TNF-alpha and IL-1, is thought to underlie endotoxin-mediated effects. Accordingly, the response of peritoneal macrophages from GM-CSF-deficient mice to LPS was studied in vitro. LPS-stimulated peritoneal macrophages from GM-CSF-deficient mice produced significantly less IL-1alpha and nitric oxide than macrophages from wild-type mice, although there was no difference in TNF-alpha production. Collectively, these observations indicate that GM-CSF contributes to cytokine production in LPS-mediated septic shock, and that the attenuated production of these secondary cytokines (IFN-gamma, IL-1alpha, and IL-6) may contribute to the endotoxin-resistant phenotype of GM-CSF-deficient mice.
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PMID:Increased tolerance to endotoxin by granulocyte-macrophage colony-stimulating factor-deficient mice. 923 38

We employed a bile duct ligation (BDL) model of cholestatic liver injury to test the hypothesis that this form of preexisting hepatic dysfunction alters the kinetics of circulating TNF-alpha and IL-6 after Escherichia coli endotoxemia, thereby augmenting mortality and lung injury by a TNF-alpha:leukotriene (LT) axis of inflammation. Male rats were catheterized 13 d after BDL or sham surgery and studied while awake 18 to 24 h later. Cholestasis after BDL was confirmed by baseline serum bilirubin (BDL = 7.34 +/- 0.72 mg/dl, mean +/- SEM, n = 17 versus Sham = 0.25 +/- 0.07, n = 20; p < 0.005) and histopathology. Sham and BDL animals received E. coli lipopolysaccharide serotype O55:B5 (LPS, 5 mg/kg i.v.) or 0.9% NaCl (NS) ending at t = 0 and were monitored over 24 h for vital signs and hemodynamics. In parallel studies, lipoxygenase inhibition was performed using diethylcarbamazine or the 5-lipoxygenase activating-protein inhibitor MK-886. Blood was collected at baseline and at t = 1.5, 3.5, and 24 h for formed elements and for serum endotoxin, TNF-alpha, IL-6, bilirubin, and alanine aminotransferase (ALT). Organs were evaluated at 24 h for histopathology, including neutrophil (PMN) densities and wet/dry weight (W/D) ratios. Cholestasis reduced survival after otherwise nonlethal endotoxemia, with seven of 11 BDL + LPS rats dying within 24 h versus no deaths in BDL + NS (n = 6), Sham + LPS (n = 14), or Sham + NS (n = 6) animals (p < 0.01). Despite equivalent serum endotoxin between groups, circulating TNF-alpha was 8-fold higher in BDL + LPS than in Sham + LPS rats at 1.5 and 3.5 h (p < 0.001), whereas serum TNF-alpha did not differ between BDL + NS and Sham + NS rats. IL-6 likewise was increased differentially by 1.5 h in BDL + LPS animals (11.98 +/- 2.42 ng/ml) versus Sham + LPS rats (3.05 +/- 0.58 ng/ml, p < 0.05). Hypothermia, bradycardic hypotension, and leukopenia were most severe and prolonged in BDL + LPS rats, which also had significantly higher ALT values, W/D ratios, and organ PMN counts. LT inhibition failed to reduce BDL-related differences in serum cytokines or survival after endotoxemia. Thus, cholestasis augments inflammatory responses to gram-negative endotoxemia, sensitizing the host to enhanced fluid flux in multiple organs and to mortality by a LT-independent mechanism.
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PMID:Cholestatic liver injury increases circulating TNF-alpha and IL-6 and mortality after Escherichia coli endotoxemia. 960 37

The results of the present study, summarized in Table 2, demonstrate that different species and strains of rodents (rats and mice) and birds (chickens) exhibit rather specific fever response. Systemic administration of LPS caused monophasic elevation in Tb of chickens, biphasic changes in Tb of rats (initial drop followed by an increase in Tb), whereas mice failed to develop hyperthermia and responded by a decreased Tb. The LPS-induced alterations in hypothalamic prostanoid synthesis were also rather species-specific and differ markedly even between the two strains of mice. We failed to find a common direct correlation between LPS-induced changes in Tb and hypothalamic prostanoid production in rodents (rats and mice). This observation is supported by our recent study on age-related changes in fever response in rats, where we found that hypothalami of LPS-treated old and young adult rats produced similar amounts of PGE2 and PGI2, in spite of more pronounced and prolonged hypothermia, and a delayed elevation in Tb of old rats, as compared with young (Fraifeld et al., 1995b). Moreover, the hypothalamus of febrile chickens did not display any detectable activation of PGE2 production, suggesting that PGE2 is not a common central mediator of fever in homeotherms (Fraifeld et al., 1995a). Apparently, the actual body temperature not always reflects the functional state of central thermostat, and increased PGE2 production in hypothalamus would not directly, at least in rodents, lead to body temperature elevation. Furthermore, peripheral effects, including PG-mediated ones, of pyrogens can interfere and even overcome their centrally-mediated effects (Morimoto et al., 1991; Burysek et al., 1993). Previously, we have shown that no additional elevation in hypothalamic PGE2 production occurs in response to doses of LPS over 10 micrograms in rats and 25 micrograms in mice, while the increased doses led to further changes in Tb response (Kaplanski et al., 1993). Morimoto et al. (1991) have considered that PGE2 acts centrally to cause fever and peripherally to cause hypothermia, and, hence, these opposing actions, both being induced by LPS, may act together to determine the final thermoregulatory response. Other possibilities could be related to counterbalance of endogenous antipyretics (Kluger, 1991; Kozak et al., 1995), that may occur not only at the level of thermoregulatory center but also outside the CNS (Klir et al., 1995), and to the existence of PG-independent mechanisms of LPS fever. The latter have been shown for IL-8 (Rothwell et al., 1990; Zampronio et al., 1994) and MIP-1 (Davatelis et al., 1989; Minano et al., 1990; Hayashi et al., 1995; Lopez-Valpuesta and Myers, 1995), which are, apparently, mediated via CRF (Strijbos et al., 1992; Zampronio et al., 1994), and INF-alpha, mediated via the opioid receptor mechanisms (Hori et al., 1991, 1992). However, it has been shown recently that in different species the same pyrogenic cytokines (IL-8) may induced fever via different, PG-independent (in rats; Zampronio et al., 1994) or PG-dependent (in rabbits; Zampronio et al., 1995) mechanisms. It should be noted that fever response is not always accompanied by an elevation in Tb. The final effect of pyrogens on body temperature depends upon the balance between heat production and heat loss, which in turn is highly dependent upon body size and ambient temperature, especially in small animals. Perhaps, the hypothermic response observed in our mice and rats at 22 degrees C may be in part attributed to ambient temperature, which was below a thermoneutral zone. The reduced febrile response is considered, at least in part, to contribute to an increased mortality and prolonged recovery from infections (Kluger, 1986). From this point, it is difficult to suggest whether the hypothermia observed in our mice and rats could be of somewhat adaptive significance. It has been shown that at the ambient temperature of 30 degrees C, Swiss Webster mice can re
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PMID:Brain eicosanoids and LPS fever: species and age differences. 963 34

Lipopolysaccharides (LPS, endotoxin) of gram-negative bacteria are among the main causes of sepsis and septic shock. In the present study, the influence of temperature on the biological activity of LPS was investigated. Lowering the temperature from 37 degrees C to 34.5 degrees C or to 30 degrees C significantly enhances in vitro tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6 release induced by different LPS chemotypes and heat-inactivated Escherichia coli. This cytokine-increasing effect of lowering the temperature is highly mediated by serum proteins, particularly by LPS-binding protein (LBP) and low-density lipoproteins (LDL). In contrast, cytokine production induced by the superantigen toxic shock syndrome toxin-1 (TSST-1) from Gram-positive Staphyloccoccus aureus decreases by around 70% at 30 degrees C as compared with 37 degrees C, corresponding to the expected effect of change in temperature and regardless of the presence of serum proteins. In order to explain the unexpected biological hypothermia effect with regard to LPS, the fluidity state of the lipid A portion of LPS as one important physico-chemical property possibly involved was investigated. The fluidity, determined by fluorescence polarization measurements, was found to decrease with decreasing temperature. These data suggest that a low fluid LPS chemotype is biologically more active than a more fluid one (and vice versa). Statistical analysis of the results shows a strong correlation between cytokine secretion and fluidity state of a given LPS chemotype (0.71 < r < 0.89, all P<0.01). As a clinical consequence, these data may be one possible explanation for the higher mortality rate of hypothermic Gram-negative sepsis.
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PMID:Hypothermia enhances the biological activity of lipopolysaccharide by altering its fluidity state. 976 Jan 71

IFNgamma potentiates the production of serum cytokines and mortality induced by LPS, but these responses do not change in parallel, and the underlying mechanisms are not clear. Pretreatment of mice with 15 microg rrIFNgamma intraperitoneally (IP) resulted in potentiation of LPS-induced serum cytokine production and hypothermia, but these changes depended on the pretreatment time and did not occur in parallel. TNFalpha and IL1beta levels showed peak potentiation after 8-h-IFNgamma pretreatment which may result from a process of sensitization of mechanisms involved in LPS responses. IL6 levels were most markedly potentiated after 3- and 6-h-IFNgamma-pretreatment and hypothermia was markedly potentiated after 0-8 h pretreatments. These effects may result from an additional synergistic action of IFNgamma with other mediators when it is present at significant levels earlier after its injection, given that IFNgamma had little (hypothermia) or no effect (cytokines) alone. The degree of potentiation induced by 18-h-IFNgamma pretreatment was related to the dose of LPS, the maximum response having been increased. Two injections of IFNgamma at 42 and 18 h prior to LPS induced greater increases in TNFalpha and IL1beta production than 18-h pretreatment alone, but not in IL6 production or hypothermia. There may be a maximum level of IL6 production which was surpassed under these conditions. These findings suggest that a balance of sensitizing and synergistic actions of IFNgamma with other mediators such as IL1 and TNFalpha, are the major mechanisms underlying its potentiation of LPS responses in mice.
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PMID:Dual mechanisms of action of interferon-gamma in potentiating responses to LPS in mice: IL1, TNFalpha and IL6 production in serum and hypothermia. 1032 86

This study tested the protective activity of antibodies to the LPS core of Haemophilus influenzae (Borrelli et al., Infect. Immun. 1995;63: 3683-92) in a hematogenous meningitis model. Meningitis was established by intraperitoneal inoculation of infant rats with H. influenzae type b (Hib). The severity of infection was determined by daily assessment of mortality, symptoms of disease and weight changes. Mortality occurred rapidly after infection with 10(5)cfu/rat and most animals died within 24 h. At a lower infection dose (10(4)cfu/rat) the rats survived, but developed symptoms of disease such as tremor, hypothermia, lethargy and anorexia within 12-72 h post challenge. Surviving animals showed decreased weight gain. Bacteremia was detected by daily blood-cultures in 10/10 rats and cleared 6 days after inoculation. The monoclonal anti-LPS antibody MAHI 3 was used in passive protection studies. MAHI 3 increased the survival in the high inoculum group (10(5)cfu/rat) from 10-17% in control animals to 60-90%. At the lower inoculum concentration (10(4)cfu/rat) MAHI 3 treatment reduced the symptoms and blood counts. Intraperitoneal injection of MAHI 3 was more effective than intranasal injection as shown by the effect on bacteremia. We conclude that anti-LPS antibodies can protect against mortality caused by hematogenous Hib infections in infant rats.
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PMID:Monoclonal anti-LPS inner core antibodies protect against experimental hematogenous Haemophilus influenzae type b meningitis. 1062 58

Patients with biliary tract obstruction have unexplained, inordinately high rates of perioperative morbidity and mortality, whereas cholestatic animals display abnormal hypothalamic responses to pyrogenic stimuli. We asked if obstructive cholestasis was associated with abnormal fever generation. Male Sprague-Dawley rats (250 g) underwent laparotomy for implantation of thermistors and either bile duct resection (BDR) or sham operation. After recovery, temperatures were recorded by telemetry and conscious, unrestrained rats in each group were injected intraperitoneally with either interleukin-1beta (IL-1beta;1 microg/kg) or Escherichia coli lipopolysaccharide (LPS; 50 microg/kg). Baseline temperatures in both groups were similar. Febrile responses after IL-1beta injection in BDR and sham groups were not significantly different. However, in response to LPS injection, BDR rats showed an initial hypothermia with a subsequently attenuated febrile response. Administration of anti-tumor necrosis factor-alpha (TNF-alpha) antibody 2 h before LPS injection blocked the LPS-induced hypothermia seen in BDR animals. However, serum levels of TNF-alpha were not significantly different between sham and BDR animals after LPS injection at any time point measured (0, 1.5, and 3 h).
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PMID:Attenuated febrile response to lipopolysaccharide in rats with biliary obstruction. 1089 60

Linking tissue uncoupling protein (UCP) homolog abundance with functional metabolic outcomes and with expression of putative genetic regulators promises to better clarify UCP homolog physiological function. A murine endotoxemia model characterized by marked alterations in thermoregulation was employed to examine the association between heat production, UCP homolog expression, and mitochondrial proton leak ("uncoupling"). After intraperitoneal lipopolysaccharide (LPS, approximately 6 mg/kg) injection, colonic temperature (T(c)) in adult female C57BL6/J mice dropped to a nadir of approximately 30 degrees C by 8 h, preceded by a four- to fivefold drop in liver UCP2 and UCP5/brain mitochondrial carrier protein 1 mRNA levels, with no change in their hindlimb skeletal muscle (SKM) expression. SKM UCP3 mRNA rose fivefold during development of hypothermia and was correlated with an LPS-induced increase in plasma free fatty acid concentration. UCP2 and UCP5 transcripts recovered about three- to sixfold in both tissues starting at 6-8 h, preceding a recovery of T(c) between 16 and 24 h. SKM UCP3 followed an opposite pattern. Such results are not consistent with an important influence of UCP3 in driving heat production but do not preclude a role for UCP2 or UCP5 in this process. The transcription coactivator PGC-1 displayed a transient LPS-evoked rise (threefold) or drop (two- to fivefold) in SKM and liver expression, respectively. No differences between control and LPS-treated mouse liver or SKM in vitro mitochondrial proton leak were evident at time points corresponding to large differences in UCP homolog expression.
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PMID:Impact of endotoxin on UCP homolog mRNA abundance, thermoregulation, and mitochondrial proton leak kinetics. 1091 45

Alterations in regional brain concentration of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their metabolites were investigated in male BALB/c mice injected intraperitoneally with bacterial lipopolysaccharide (LPS, 2 mg kg(-1)) or recombinant murine tumor necrosis factor alpha (TNFalpha, 0.1 mg kg(-1)) at 2, 6, 12 and 24 h after the injection. At 2 h post-injection the LPS administration resulted in hypothermia, which was not apparent at later time points. No consistent effects were observed by either LPS or TNFalpha on peripheral leukocyte counts or plasma transaminase levels. Both LPS and TNFalpha slightly elevated NE metabolism in the striatum at 2-12 h. Concentrations of DA and its metabolites were significantly elevated only in the hypothalamus following TNFalpha at 24 h. Tumor necrosis factor alpha exerted pronounced effects on 5-HT metabolism in most brain regions at 2 h. Results suggest that the effect of LPS is more complex compared with TNFalpha because of the endogenous production of other cytokines including the TNFalpha.
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PMID:Effects of endotoxin and tumor necrosis factor alpha on regional brain neurotransmitters in mice. 1094 81

Perinatal brain damage in the mature fetus is usually brought about by severe intrauterine asphyxia following an acute reduction of the uterine or umbilical circulation. The areas most heavily affected are the parasagittal region of the cerebral cortex and the basal ganglia. The fetus reacts to a severe lack of oxygen with activation of the sympathetic-adrenergic nervous system and a redistribution of cardiac output in favor of the central organs (brain, heart and adrenals). If the asphyxic insult persists, the fetus is unable to maintain circulatory centralization, and the cardiac output and extent of cerebral perfusion fall. Owing to the acute reduction in oxygen supply, oxidative phosphorylation in the brain comes to a standstill. The Na+/K+ pump at the cell membrane has no more energy to maintain the ionic gradients. In the absence of a membrane potential, large amounts of calcium ions flow through the voltage-dependent ion channels, down an extreme extra-/intracellular concentration gradient, into the cell. Current research suggests that the excessive increase in levels of intracellular calcium, so-called calcium overload, leads to cell damage through the activation of proteases, lipases and endonucleases. During ischemia, besides the influx of calcium ions into the cells via voltage-dependent calcium channels, more calcium enters the cells through glutamate-regulated ion channels. Glutamate, an excitatory neurotransmitter, is released from presynaptic vesicles during ischemia following anoxic cell depolarization. The acute lack of cellular energy arising during ischemia induces almost complete inhibition of cerebral protein biosynthesis. Once the ischemic period is over, protein biosynthesis returns to preischemic levels in non-vulnerable regions of the brain, while in more vulnerable areas it remains inhibited. The inhibition of protein synthesis, therefore, appears to be an early indicator of subsequent neuronal cell death. A second wave of neuronal cell damage occurs during the reperfusion phase. This cell damage is thought to be caused by the postischemic release of oxygen radicals, synthesis of nitric oxide (NO), inflammatory reactions and an imbalance between the excitatory and inhibitory neurotransmitter systems. Part of the secondary neuronal cell damage may be caused by induction of a kind of cellular suicide programme known as apoptosis. Interestingly, there is increasing evidence from recent clinical studies that perinatal brain damage is closely associated with ascending intrauterine infection before or during birth. However, a major part of this damage is likely to be of hypoxic-ischemic nature due to LPS-induced effects on fetal cerebral circulation. Knowledge of these pathophysiological mechanisms has enabled scientists to develop new therapeutic strategies with successful results in animal experiments. The potential of such therapies is discussed here, particularly the promising effects of intravenous administration of magnesium or postischemic induction of cerebral hypothermia.
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PMID:Perinatal brain injury. 1123 23


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