Fever In Mice Research Articles

Interaction between inhibitors of inducible nitric oxide synthase and cyclooxygenase in Brewer's yeast induced pyrexia in mice: An isobolographic study

We studied the interaction of S-methylisothiourea (a selective inducible nitric oxide synthase inhibitor) with rofecoxib (selective cyclooxygenase-2 inhibitor) and mefenamic acid (non-selective cyclooxygenase inhibitor) in Brewer's yeast-induced pyrexia in mice by isobolographic analysis. Each drug was effective in reducing pyrexia when used alone. Log–dose–response curves of all the three drugs did not show any significant departure from parallelism indicating thereby, a common mode of antipyretic action. However, rofecoxib exhibited significantly higher potency than S-methylisothiourea. Isobolographic analysis of combination of S-methylisothiourea with rofecoxib and mefenamic acid revealed additive interaction. Experimental ED 50 of the combinations was not significantly different from theoretical additive ED 50 of the corresponding drug combination, that substantiated the additive nature of interaction between inducible nitric oxide synthase and cyclooxygenase in Brewer's yeast-induced fever in mice. Results suggest involvement of a mediator that is subservient to both inducible nitric oxide synthase and cyclooxygenase-2 enzyme activities. For further investigation, peroxynitrite ion may be considered to be the putative mediator.

Generation of a complement-independent bactericidal IgM against a relapsing fever Borrelia.

The spirochetemia of relapsing fever in mice is cleared by a complement-independent, polyclonal IgM response with reactivity to two prominent Ags of 20 and 35 kDa. In this study, we have dissected the polyclonal IgM Ab response against a relapsing fever spirochete to determine the specificity of its complement-independent bactericidal properties. Our experimental approach selectively generated an IgM murine mAb from the early specific immune response to a variable outer membrane protein. This IgM is bactericidal in the absence of complement and is part of the polyclonal Ab response that mediates the clearance of this bacterium from the blood. Purified monoclonal IgM caused direct structural damage to the outer membrane of the spirochete, in the absence of complement, and protected both B cell- and C5-deficient mice from challenge when administered passively. The direct, complement-independent, bactericidal activity of Abs is a critical mechanism of host defense against infection.

Genetic Models in Applied Physiology. Differential role of nitric oxide synthase isoforms in fever of different etiologies: studies using Nos gene-deficient mice.

Male C57BL/6J mice deficient in nitric oxide synthase (NOS) genes (knockout) and control (wild-type) mice were implanted intra-abdominally with battery-operated miniature biotelemeters (model VMFH MiniMitter, Sunriver, OR) to monitor changes in body temperature. Intravenous injection of lipopolysaccharide (LPS; 50 microg/kg) was used to trigger fever in response to systemic inflammation in mice. To induce a febrile response to localized inflammation, the mice were injected subcutaneously with pure turpentine oil (30 microl/animal) into the left hindlimb. Oral administration (gavage) of N(G)-monomethyl-l-arginine (l-NMMA) for 3 days (80 mg. kg(-1). day(-1) in corn oil) before injection of pyrogens was used to inhibit all three NOSs (N(G)-monomethyl-d-arginine acetate salt and corn oil were used as control). In normal male C57BL/6J mice, l-NMMA inhibited the LPS-induced fever by approximately 60%, whereas it augmented fever by approximately 65% in mice injected with turpentine. Challenging the respective NOS knockout mice with LPS and with l-NMMA revealed that inducible NOS and neuronal NOS isoforms are responsible for the induction of fever to LPS, whereas endothelial NOS (eNOS) is not involved. In contrast, none of the NOS isoforms appeared to trigger fever to turpentine. Inhibition of eNOS, however, exacerbates fever in mice treated with l-NMMA and turpentine, indicating that eNOS participates in the antipyretic mechanism. These data support the hypothesis that nitric oxide is a regulator of fever. Its action differs, however, depending on the pyrogen used and the NOS isoform.

Early events in the pathogenesis of avian salmonellosis.

Salmonellae are gastrointestinal pathogens of man and animals. However, strains that are host-specific avian pathogens are often avirulent in mammals, and those which are nonspecific are commensal in poultry. The objective of this study was to determine whether host specificity was exhibited by bacterial abilities to invade epithelial cells or resist leukocyte killing. In this study, leukocytes isolated from humans and chickens were used to kill Salmonella in vitro. Both Salmonella pullorum, an avian-specific serotype, and Salmonella typhimurium, a broad-host-range serotype, were sensitive to killing by polymorphonuclear leukocytes isolated from both species. Both serotypes replicated in cells of the MQ-NCSU avian-macrophage cell line. In contrast, S. pullorum was noninvasive for cultured epithelial Henle 407, chick kidney, chick ovary, and budgerigar abdominal tumor cells. In the bird challenge, however, S. typhimurium rapidly caused inflammation of the intestinal mucosa, but S. pullorum preferentially targeted the bursa of Fabricius prior to eliciting intestinal inflammation. Salmonella serotypes which cause typhoid fever in mice have been shown to target the gut-associated lymphoid tissue. Observations from this study show that S. pullorum initiated a route of infection in chicks comparable to the route it takes in cases of enteric fever.

Inhibitors of alternative pathways of arachidonate metabolism differentially affect fever in mice.

Inhibitors of cyclooxygenases prevent fever. The purpose of this study was to test the hypothesis that selective and dual inhibitors of the other enzyme systems of arachidonic acid oxygenation (i.e., lipoxygenase and epoxygenase) affect the time course or magnitude of fever in mice. Swiss Webster mice kept at 30 degreesC ambient temperature were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide at doses from 10 micrograms/kg to 2.5 mg/kg. Phenidone (20-30 mg/kg ip), a dual lipoxygenase and cyclooxygenase inhibitor, prevented fever in these mice, but esculetin (1-10 mg/kg ip), a selective inhibitor of lipoxygenases, did not affect fever. Intramuscular injection of nordihydroguaiaretic acid (10-20 mg/kg), a dual lipoxygenase and epoxygenase inhibitor, as well as SKF-525A (5 mg/kg ip) and clotrimazole (20 mg/kg im), inhibitors of the cytochrome P-450/epoxygenase pathway, augmented fever in mice. Indomethacin (5 mg/kg ip), an inhibitor of cyclooxygenase, suppressed the exacerbation of fever due to clotrimazole, suggesting that the epoxygenase inhibitor-induced potentiation of fever in mice is a prostaglandin-mediated effect. From this study, we hypothesize that the cytochrome P-450/epoxygenase branch of the arachidonate cascade is involved in antipyresis and in controlling the upper limit of fever.

Role of IL-10 in inflammation. Studies using cytokine knockout mice.

Interleukin-10 (IL-10) inhibits the synthesis of proinflammatory cytokines known to be involved in fever, including IL-1, IL-6, and tumor necrosis factor-alpha. We hypothesized that IL-10 modulates lipopolysaccharide (LPS)-induced fever in mice. Body temperature was measured by biotelemetry. Swiss Webster mice injected with recombinant murine IL-10 (rmuIL-10) were resistant to fever induced by a low dose of LPS (100 micrograms/kg, i.p.) and to the hypothermic and febrile effects of a high (septic-like) dose of LPS (2.5 mg/kg, i.p.). Injection of rmuIL-10 alone had no effect on afebrile body temperature of Swiss Webster mice. IL-10 knockout mice showed an exacerbated and prolonged fever in response to a low dose of LPS (50 micrograms/kg, i.p.) compared to their wild-type counterparts. These data support the hypothesis that IL-10 acts as an endogenous cryogen during LPS-induced fever in mice.

Dendritic cells of the murine Peyer's patches colocalize with Salmonella typhimurium avirulent mutants in the subepithelial dome.

Salmonella typhimurium is an enteropathogenic bacterium that invades the murine Peyer’s patches (PP), the mucosal lymphoid tissue of the small intestine (1), and later spreads systemically resulting in a disease similar to typhoid fever in mice (2).KeywordsDendritic CellTyphoid FeverIntracellular BacteriumOral ImmunizationWild Type BacteriumThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

TNF soluble receptor and antiserum against TNF enhance lipopolysaccharide fever in mice.

We tested the effects of tumor necrosis factor (TNF) soluble receptor (sTNFR) and anti-TNF serum (anti-TNF) administered intraperitoneally on fever induced by lipopolysaccharide (LPS) in mice. Both agents have been shown to block bioactivity of mouse TNF-alpha. Core temperature (Tb) and locomotor activity in unrestrained mice were measured by biotelemetry. Within 1 h from the LPS injection (2.5 mg/kg ip) Tb decreased below normal for 5-6 h and motor activity was depressed for the following 48 h. After this initial reduction, Tb increased and reached a peak at approximately 24 h postinjection. Anti-TNF and sTNFR blocked this "hypothermic phase" after LPS, and the fevers started sooner; however, the levels and time of peak temperature did not change markedly. In addition, a human recombinant TNF-alpha given intraperitoneally abolished fever and prolonged the fall of Tb in mice after LPS. We conclude that the reduction of Tb soon after injection of LPS in mice is dependent on TNF-alpha.

Effects of malaria on O2 consumption and brown adipose tissue activity in mice.

Increased energy expenditure often occurs during illness or after injection of endotoxin and can contribute to the generation of fever. In laboratory rats and mice the thermogenic response has been attributed to the sympathetic activation of brown adipose tissue (BAT), although mice often fail to show pyrexia. In this study the effects of malaria on O2 consumption and BAT were studied in mice inoculated with Plasmodium berghei. Parasitemia was maximal (greater than 50% of erythrocytes showing positive Leishman staining) 72 h after inoculation. Up to this time body weight and food intake were similar to values for control mice, although colonic temperatures were slightly depressed in infected mice. Thereafter, infected mice showed marked hypophagia, loss of body weight, and severe hypothermia; colonic temperature was less than 31 degrees C at 96 h when the experiment was terminated. Resting O2 consumption (VO2) measured at 24 degrees C was slightly elevated in infected mice 12 h after inoculation and reached a peak value (31% above controls) at 48 h. VO2 returned to the same value as controls at 96 h. In vitro thermogenic activity of BAT (assessed from binding of guanosine diphosphate to isolated mitochondria) was not significantly altered in infected mice. These data demonstrate a marked thermogenic response to malarial infection, but this is not accompanied by fever in mice and is dissociated from stimulation of BAT activity.

Cleavage of human interleukin 1: isolation of a peptide fragment from plasma of febrile humans and activated monocytes.

Interleukin 1 (IL 1) is a product(s) of mononuclear phagocytes, and has multiple biologic activities that mediate several host responses to infection and inflammation. Highly purified IL 1 activates lymphocytes, induces fever, increases hepatic acute phase protein synthesis, and increases muscle protein degradation. A 4.2 kd peptide has been purified from plasma of febrile humans which also induces muscle proteolysis in vitro (termed proteolysis-inducing factor, PIF). Because IL 1 purified from activated human monocytes induces muscle proteolysis in vitro, studies were performed to determine the relationship of human monocyte-derived IL 1 to plasma-derived PIF. Purified PIF was highly active in the IL 1 thymocyte assay. After gel filtration of plasma from febrile patients, fractions with PIF activity also induced thymocyte proliferation and fever in mice. Thus, it seems likely that the plasma peptide PIF has IL 1 properties and probably represents a small m.w. cleavage product of IL 1. Further studies confirmed this finding. Highly purified 15 kd IL 1, rechromatographed over different gel filtration media, consistently fragmented into a 4 kd peptide with both muscle proteolysis-inducing and lymphocyte-activating properties. The breakdown of the 15 kd IL 1 into biologically active smaller fragments increased with time, and could be accelerated by trypsinization. The monocyte-derived IL 1 fragments were partially destroyed by heat. Highly purified 125I-labeled 15 kd IL 1 also fragmented into subunits, and these radioactive subunits produced fever in mice and were active in the thymocyte assay. Fragmentation of 125I-labeled 15 kd IL 1 was reduced by agents that inhibit proteases. These results indicate that some of the biologic activities of human IL 1 are conserved in small m.w. fragments. These studies also provide evidence that IL 1 may circulate in humans as a 4.2 kd peptide, and that this cleavage product can function as an active mediator of IL 1 effects in the host.

The mutagenic potential of hyperthermia and fever in mice

The cytogenetic effects of hyperthermia resulting from climatic influences as well as from infections were studied. Whole-body exposure of NMRI mice to an elevated environmental temperature induced a high frequency of micronucleated polychromatic erythrocytes in bone marrow. Hyperthermia at high relative humidity was more effective in increasing body temperature and cytogenetic damage than at low RH. A sex-related difference in response to heat stress was observed. Hyperthermia on pregnant mice induced a significant increase in the incidence of micronucleated PEs in fetal blood cells. Parenteral administration of bacterial endotoxin, lipopolysaccharides, induced either hypothermia or hyperthermia. However, LPS-induced hypothermia as well as fever does not so far appear to produce cytogenetic damage.

The pyrogenic and mitogenic actions of interleukin-1 are related.

Our present understanding of the pathogenesis of fever is that host macrophages, following activation by an appropriate stimulus such as Gram-negative lipopolysaccharide (LPS) immune complexes, or primed lymphocytes in the presence of specific antigen, synthesize and release endogenous pyrogen (EP). EP is carried in the blood circulation to the hypothalamic area of the brain where its action, involving a protein synthetic step, results in an increase of the level at which body temperature is maintained. Recently, it was shown that EP is very similar and possibly identical to another macrophage mediator previously called lymphocyte activating factor and now known as interleukin-1 (IL-1) which, in conjunction with lectin or specific antigen, induces clonal expansion of T lymphocytes. We show here that murine T-cell proliferation in response to IL-1 in vitro is greatly increased when the cells are exposed to a temperature typical of fever and that injection of the same IL-1 causes fever in mice. If this relationship exists in vivo, the resulting facilitation of a T-cell-dependent immune response may well confer survival value and contribute to the evolutionary conservation of fever--a phylogenetically ancient response to infection.

A new sensitive method for detecting human endogenous (leukocyte) pyrogen.

Endogenous, or leukocyte pyrogen (EP), the mediator of fever, is currently detected by injection of pyrogen-containing supernatants into rabbits. This assay has been of little value in the study of human fever because it required injection of relatively large amounts of pyrogen. We now report that injection of medium containing human EP produces fever in mice. Supernatant from 1 c 10(5) granulocytes, stimulated by phagocytosis of staphylococci and incubated overnight, or 1 x 10(4) monocytes similarly treated, produce clear pyrogenic responses. This method for detecting EP is about 100-fold more sensitive than the rabbit assay, and it appears to be specific for EP. Preliminary studies of EP released by small samples of needle liver biopsies from febrile and afebrile patients suggests that this sensitive assay may be useful for investigations into the mechanisms of clinical fever.

Pyrogen from mouse macrophages causes fever in mice.

Mouse peritoneal macrophages, after phagocytosis, release an endogenous (leucocyte) pyrogen. Intravenous injection of stimulated cell culture supernatant produces a prompt, monophasic fever in mice maintained in a 35 degree environment. The pyrogen is distinct from endotoxin, and resembles cell pyrogens of other species in heat-lability and pronase sensitivity. Human leucocyte pyrogen produces identical responses in mice. Measurement of fever in mice appears to provide a sensitive biological assay for endogenous pyrogens.

2-Deoxy-D-glucose inhibition of prostaglandin E1 hyperthermia and yeast fever in mice.

2-Deoxy-D-glucose (2-DG) and sodium salicylate were evaluated relative to their effects on body temperature in mice with prostaglandin E1 (PGE1)hyperthermia or yeast fever. Injection of 2-DG into the cerebral ventricles of conscious mice abolished the hyperthermia of PGE1 and reduced the fever produced by yeast, while sodium salicylate was effective only in yeast fever. The data are suggestive of glucose dependency of thermoregulatory centers in the brain.

Mouse hepatitis virusに関する研究 (第1報)

During the past 6 years 6 strains of hepatotropic virus of mice have been described. Some of them appear to be related to each other serologically.The present mouse hepatitis virus (Buescher's EHF-120) was encountered during attempts to establish the agents of hemorrhagic fever in mice by serial blind passage of viscera.The purpose of this communication is to give some account of the disease produced in mice by this virus and to describe its general properties.Acute hepatitis was regularly reproducible in mice by the intraperitoneal injection of liver suspensions from dead or moribund mice. Infected mice showed a ruffled coat, “hunched” posture, and fine tremors before death. The incubation period was usually about 30 hours and the desth was occured between 2nd and 3rd day. The urine was staining some times the coat in the perineal region, but there was no external indication of jaundice.On post-mortem examination the most striking abnormality was found in the liver. Liver was pale yellow and mottled with petechial hemorrhages. In other organs there was no obvious lesion.The distribution of the virus in several viscera after intraperitoneal injection was determined and the high concentration was proved in liver and brain. The virus was also found in the spleen, kidney, lung, , intestine and blood of the infected mice at the death or moribund stage.Other inoculation procedures were also examined. The mice were infected by intracerebral, intranasal, subcutaneous, intravenous, per os, and food pad inoculation. Gross pathological changes in the liver were seen in all dead mice, irrespective of the route of inoculation, suggesting a hepatotropic character of this virus.The virus survies heating at 60°C for 30 minutes and exposure to ultraviolet-irradiation at the distance of 9cm from the lamp for 5 minutes. The activity of the infected liver in 50 per cent glycerol was retained on storage in the refrigerator for intervals up to 2 months. The filtrate of the liver suspension through Seitz EK filter was also infectious.Attempts were made to infect rats, guinea-pigs, hamster, and rabbits by intraperitoneal or intravenous inoculation of infected mouse liver extract, but no symptoms or lesions were produced in these species.The chorioallantois of 9 to 13 day old chick embryos was inoculated with infected mouse liver. After 48 to 72 hours' incubation at 36°C discrete white foci were noticed on these membranes at least at the beginning of this experiment. On continued passage, the numder of foci produced decreased progressively. Although the virus was detectable in the chickembryo liver and on the membranes by mice inoculation in the 1st to 4th passge, it became impossible afterwards.

Chemotherapy of Experimental Relapsing Fever in Mice with Antibiotics and Synthetic Compounds

In a search for new antispirochetal agents, four antibiotics and 206 synthetic compounds were examined by testing their ability to suppress the spirochetemia in standardized relapsing fever infections in mice. Subtilin, methylated subtilin, bacitracin, and Melarsen oxide were found to be very effective.

Q FEVER—A REVIEW OF CURRENT KNOWLEDGE

Excerpt Q fever is an acute specific, often serious, and occasionally fatal rickettsial disease of man. It is characterized by a high fever, headache and malaise and is often misdiagnosed as influe...

The Histopathology of Experimental "Q" Fever in Mice

The Histopathology of Experimental "Q" Fever in Mice