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 unique germfree, colostrum-deprived, immunologically "virgin" piglet model was used to evaluate the ability of lactoferrin (LF) to protect against lethal shock induced by intravenously administered endotoxin. Piglets were fed LF or bovine serum albumin (BSA) prior to challenge with intravenous Escherichia coli lipopolysaccharide (LPS), and temperature, clinical symptoms, and mortality were tracked for 48 h following LPS administration. Prefeeding with LF resulted in a significant decrease in piglet mortality compared to feeding with BSA (16.7 versus 73.7% mortality, P < 0.001). Protection against the LPS challenge by LF was also correlated with both resistance to induction of hypothermia by endotoxin and an overall increase in wellness, as quantified by a toxicity score developed for these studies. In vitro studies using a flow cytometric assay system demonstrated that LPS binding to porcine monocytes was inhibited by LF in a dose-dependent fashion, suggesting that the mechanism of LF action in vivo may be inhibition of LPS binding to monocytes/macrophages and, in turn, prevention of induction of monocyte/macrophage-derived inflammatory-toxic cytokines.
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PMID:The protective effects of lactoferrin feeding against endotoxin lethal shock in germfree piglets. 952 62

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

We measured body temperature in Pekin ducks for 22 h after intravenous injection of the lipopolysaccharide (LPS) of gram negative bacteria at doses of 0, 1, 10, and 100 micrograms.kg body mass (-1). The ducks developed monophasic fevers showing increases in peak temperature reached and duration of fever with increases in dose of LPS. Body temperatures of unrestrained telemetered ducks without access to food and water were similar to those of saline-injected controls in the fever experiments, but were lower in the morning than when the same birds had access to food and water. This nocturnal hypothermia may have resulted from energy restriction imposed by lack of food and water. The dose of LPS required to elicit a fever of over 18 h duration (100 micrograms.kg-1) will elicit a biphasic fever of 5 h duration in rats. Pekin ducks did not exhibit biphasic fever even at the highest LPS dose administered, indicating that while fever is superficially similar in the two homeothermic classes, there may be differences in details of the mechanism. The similarities of the dose/response characteristics to that of mammals lends support to the theory that fever in vertebrates has a common phyletic origin.
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PMID:Characteristics of the febrile response in Pekin ducks. 963 56

1. Bacterial lipopolysaccharide (LPS)-induced increases in serum cytokines (TNF-alpha, IL-1 and IL-6) and hypothermia were studied in mice sensitized by carrageenan pretreatment and compared with mice sensitized with heat-killed P. acnes or IFN-gamma, all given IP at appropriate intervals (24 hr, 7 days and 12-18 hr, respectively) before LPS. 2. In mice with localized peritoneal inflammation induced by carrageenan, peak TNF-alpha levels (1.5-2 h after LPS) were markedly enhanced after both doses of LPS tested (50 and 200 microg/mouse IP). However, IL-1beta levels were not changed and IL-6 levels were decreased only after the higher dose of LPS. Hypothermia showed weak and inconsistent changes in carrageenan-sensitized mice. 3. IL-1beta levels in spleen lysates were higher but paralleled those in the serum, being increased in IFN-gamma-sensitized but not in carrageenan-sensitized mice. The levels of both TNF-alpha and IL-1beta were high in the peritoneum of carrageenan-sensitized mice, suggesting that the increased serum TNF-alpha did not emanate from the peritoneum. 4. In mice sensitized with the other two agents, as expected, the levels of all three cytokines increased, but peak levels were attained at the same times post-LPS (TNF-alpha: 1-1.5 hr; IL-1: 3-4 hr; IL-6: 3-4 hr). In addition, hypothermia was increased with both of these methods of sensitization. 5. The lack of consistent correlation of the levels of cytokines studied, particularly TNF-alpha, with the degree of hypothermia, raises questions as to their causative role in its induction in these models. 6. The mechanisms underlying these models of sensitization are clearly different, and further understanding of these mechanisms would aid in the interpretation of the effects of drugs in the models.
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PMID:Selective enhancement of LPS-induced serum TNF-alpha production by carrageenan pretreatment in mice. 968 77

Recent studies have shown that perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) alters thermoregulatory function in adult rats and hamsters, indicated by a reduced body temperature during the animal's nocturnal phase. The present study was designed to assess the behavioral thermoregulation, ability to develop a fever, and thermoregulatory stability as a function of ambient temperature (Ta) in rats exposed perinatally to TCDD. Pregnant Long-Evans rats were exposed on gestational day (GD) 15 to 1 microg TCDD/kg (po). The male offspring were implanted with transmitters to monitor core temperature (Tc) and motor activity (MA). The 24-h pattern of core temperature was affected by TCDD exposure, characterized by a reduced nocturnal Tc. At some ages, the diurnal Tc of the TCDD group was elevated. This dysfunction in temperature regulation was most apparent at 7 and 11 mo of age. The 24-h pattern of MA was also altered by TCDD. The hypothermic effects of TCDD were most pronounced at cooler Ta values of 10 to 22 degrees C. In contrast, behavioral thermoregulation, assessed by measuring the selected Ta and Tc of rats in a temperature gradient, was unaffected by TCDD. The ability to develop a fever following administration of lipopolysaccharide (LPS) endotoxin (Escherichia coli; 50 microg/kg) was accentuated in the TCDD-treated animals. The data confirm a nocturnal hypothermia in rats prenatally exposed to TCDD. However, the normal behavioral regulation of Tc suggests that hypothalamic thermoregulatory centers are not permanently altered. The accentuated fever in TCDD animals shows possible functional alterations in the neuroimmune and/or thermoregulatory axes involved in fever.
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PMID:Thermoregulation in rats exposed perinatally to dioxin: core temperature stability to altered ambient temperature, behavioral thermoregulation, and febrile response to lipopolysaccharide. 972 85

The ability of the second generation phosphodiesterase 4 inhibitor SB 207499 (Ariflo), [c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexane carboxylic acid], to inhibit inflammatory cytokine production in vivo was evaluated and compared to that of rolipram, a first generation phosphodiesterase 4 inhibitor. To examine human tumor necrosis factor alpha (TNFalpha) production, human monocytes were adoptively transferred into Balb/c mice and challenged with lipopolysaccharide (LPS). In this model, SB 207499 inhibited human TNFalpha production with oral ED50 of 4.9 mg/kg. Similarly, R-rolipram inhibited human TNFalpha production with an ED50 of 5.1 mg/kg, p.o. In contrast to their equipotent activity against TNFalpha production, SB 207499 (ED50 = 2.3 mg/kg, p.o.) was 10-fold less potent than R-rolipram (ED50 = 0.23 mg/kg, p.o.) in reversing reserpine-induced hypothermia, a model of antidepressant activity. In time course studies, SB 207499 (30 mg/kg, p.o.) inhibited TNFalpha production for at least 10 hr; substantial plasma concentrations of SB 207499 were detected over the same interval. The ability of SB 207499 to modulate interleukin-4 production in vivo was assessed in a chronic oxazolone-induced contact sensitivity model in Balb/c mice. In this model, topical administration of SB 207499 (1000 microgram) inhibited intralesional concentrations of interleukin-4 (55%; P <.01). The results demonstrate that SB 207499 is a potent inhibitor of inflammatory cytokine production in a variety of settings in vivo. Moreover, although it is as potent as R-rolipram in inhibiting TNFalpha production, it has substantially less central nervous system activity. Thus SB 207499 represents an excellent candidate with which to evaluate the antiinflammatory potential of PDE4 inhibitors.
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PMID:SB 207499 (Ariflo), a second generation phosphodiesterase 4 inhibitor, reduces tumor necrosis factor alpha and interleukin-4 production in vivo. 980

Oral chlorpyrifos (CHP) induces hypothermia followed by a fever that persists for several days in the rat. To understand the neuro-immune mechanisms of CHP-induced fever, we compared the tolerance and cross-tolerance between CHP and the fever elicited by lipopolysaccharide (LPS) (Escherichia coli). Female rats were administered the corn oil (CO) vehicle or CHP (10 mg/kg; p.o.) daily for 4 days while core temperature (Tc) and motor activity (MA) were monitored by telemetry. There was a reduction in Tc followed by an elevation the next day after each CHP treatment. The day after the last CHP treatment, rats were administered saline or 50 microg/kg LPS (i.p.). CHP-treated rats had a smaller LPS fever that was attributed to their elevated baseline Tc. In another study, rats were dosed with saline or LPS daily for three days. By the time of the third LPS injection there was no febrile response, indicating tolerance to LPS. Rats were then dosed with CO or CHP (10 mg/kg) 24 h after the third LPS treatment. LPS-tolerant rats displayed an accentuated hypothermic and febrile response to CHP. Plasma cholinesterase activity was unaffected by repeated LPS treatment, suggesting that the metabolism of CHP in the liver was unaffected by LPS. Overall, the neural-immune mechanisms for LPS fever is distinct from that of CHP in view of marked difference in mechanisms of tolerance.
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PMID:Delayed febrile effects of chlorpyrifos: is there cross-tolerance to bacterial lipopolysaccharide? 984 93

Septic episodes in thermal injuries are usually hallmarked by a series of physiologic parameters that include tachypnea, prolonged paralytic ileus, hyperthermia or hypothermia, altered mental status, thrombocytopenia, leukocytosis or unexplained leukopenia, acidosis, and hyperglycemia. Recent studies with polycystic kidney disease have clearly indicated that the limulus amebocyte lysate (LAL) assays were predictive of fungal infections in this patient population. Because both bacteria and fungi produce lipopolysaccharide that can be identified with the LAL assay, we randomly assayed sequential sera of 45 patients with major thermal injuries for positivity in the LAL assay, with use of the QCL-1000 kit (BioWhittaker, Walkersville, Md). The average burn size of this patient population was 63.43% total body surface area. The average age of the patient was 6.2 years. The sex distribution included 30 males and 15 females. The infectious agents included gram-positive cocci and gram-negative rods, and 14 patients had concomitant fungal infections. Eighty-five percent of the patients tested were positive for endotoxin, with levels ranging from < 0.1 EU/mL to > 1.0 EU/mL. The predominant organism isolated before or on the date the serum was drawn was Pseudomonas aeruginosa (51%), followed by Klebsiella pneumoniae (15%). The remaining 34% were a variety of Enterobacteriaceae. Of the 14 patients who yielded a fungus, 3 had negative LAL assays. Two patients with an elevated LAL grew only Staphylococcus epidermidis in the bloodstream and the wounds. These data clearly indicate that the LAL assay cannot be relied on as the sole predictor of septic episodes; however, it can be an adjunctive test to confirm sepsis when the other parameters have been considered.
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PMID:Is the limulus amebocyte lysate the sole predictor of septic episodes in major thermal injuries? 984 41

The aim of the present study was to examine a possible involvement of leukotrienes (LTs) in lipopolysaccharide (LPS)-induced body temperature (Tb) response. We examined the effect of MK-886, an inhibitor of LT synthesis, on changes in Tb, plasma tumor necrosis factor-alpha (TNF-alpha), hypothalamic LT, and PGE2 production. Intraperitoneal injection of LPS (50 microgramg/mouse) led to a decrease in Tb starting 1 h after the injection. The hypothermic effect of LPS was accompanied by a significant elevation in TNF-alpha level in plasma and in LT and PGE2 production by ex vivo-incubated hypothalamus. MK-886 (1 mg/kg ip) administered 4 h before LPS efficaciously prevented LPS-induced hypothermia in mice. Pretreatment of mice with MK-886 did not alter the LPS-stimulated increase in plasma TNF-alpha. MK-886 significantly inhibited LT and enhanced PGE2 production in hypothalamus compared with LPS alone. These results suggest that 1) LPS-induced hypothermia may be mediated by LTs and 2) the antihypothermic effect of MK-886 is not associated with TNF-alpha bioactivity.
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PMID:Evidence supporting involvement of leukotrienes in LPS-induced hypothermia in mice. 988 77

Interleukin (IL)-10 inhibits the synthesis of proinflammatory cytokines implicated in fever, including IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. We hypothesized that IL-10 functions as an antipyretic in the regulation of fevers to lipopolysaccharide (LPS) and turpentine. Body temperature was measured by biotelemetry. Swiss Webster (SW) mice treated with recombinant murine IL-10 were resistant to fever induced by a low dose of LPS (100 microgram/kg ip) and to the hypothermic and febrile effects of a high (septiclike) dose of LPS (2.5 mg/kg ip). IL-10 knockout mice developed an exacerbated and prolonged fever in response to a low dose of LPS (50 microgram/kg ip) compared with their wild-type counterparts. At 4 h after injection of the low dose of LPS, plasma levels of IL-6, but not TNF-alpha, were significantly elevated in the IL-10 knockout mice compared with their wild-type controls (ANOVA, P < 0.05). After injection of the same high dose of LPS injected into SW mice, wild-type mice developed a fever at 24 h whereas IL-10 knockout mice immediately developed a profound hypothermia that lasted through 41 h (ANOVA, P < 0.05). Body weight and food intake were more significantly depressed in response to the high dose of LPS in the knockout mice compared with their wild-type controls. Only 30% of the IL-10 knockout mice survived compared with 100% of the wild-type mice (Fisher's exact test, P < 0.05). Fever in response to the injection of turpentine (100 microliter/mouse sc) did not differ between wild-type and IL-10 knockout mice. These data support the hypotheses that 1) IL-10 functions as an endogenous antipyretic following exposure to LPS, 2) a putative mechanism of the early antipyretic action of IL-10 is through the inhibition of plasma levels of IL-6, 3) IL-10 has a protective role in the lethal effects of exposure to high levels of LPS, and 4) endogenous IL-10 does not have a role in fever induced by turpentine.
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PMID:An antipyretic role for interleukin-10 in LPS fever in mice. 988 80


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