Fever in rats during normal and dehydrated conditions

The effect of endogenous pyrogen (EP, from rabbit) and endotoxin (Salmonella typhosa) on rectal temperature (Tre) was investigated in normal and dehydrated rats of both sexes. Intraperitoneal injection of either EP or endotoxin did not affect body temperature. In addition, no changes in Tre were observed when endotoxin was injected intravenously in normally hydrated male rats, but significant falls in Tre occurred in normal female rats. However, intravenous injection of EP produced fever in both sexes, but females generally showed smaller responses. A second intravenous injection of endotoxin, given 3 days after the first injection, always produced fever in normally hydrated rats. The pattern of this febrile response was monophasic. In contrast to the response in normal rats, intravenous endotoxin produced significant fevers with a biphasic pattern in dehydrated rats of either sex, but the febrile responses of male rats were greater than those of female rats. On the other hand, there were no significant differences between febrile responses to intravenous EP exhibited by normal and dehydrated animals. These results show that rats of both sexes possess physiological mechanisms capable of producing a fever following intravenous injections of EP.     

Evidence for a novel circulating alpha 1 protein in tumour-bearing rats. Differentiation from acute phase alpha 1 proteins and from alpha 1 fetoprotein

It has been found in this study that the serum from rats bearing a transplanted dibenzanthracene-induced tumour ($\text{RD}\text{3}$), has a high concentration of alpha₁ proteins compared with normal rat serum. These alpha₁ proteins have been isolated by an immunoabsorption method and have been compared by immunological methods with the acute phase alpha₁ proteins isolated by the same method from the serum of rats presenting an inflammatory reaction. It has been found that the isolated $\text{RD}\text{3}$ alpha₁ proteins were composed of two major proteins: one of these corresponded to an inflammatory protein, the alpha₁-AP-globulin. The other may be a new protein, as it is absent from the serum of rats with an acute phase inflammatory reaction and nor does it correspond to alpha₁ feto-protein, a carcino-embryonic protein presenting the same electrophoretic mobility.     

Acute Binge Drinking Increases Serum Endotoxin and Bacterial DNA Levels in Healthy Individuals

Binge drinking, the most common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its biological consequences are poorly defined. Previous studies demonstrated that chronic alcohol use results in increased gut permeability and increased serum endotoxin levels that contribute to many of the biological effects of chronic alcohol, including alcoholic liver disease. In this study, we evaluated the effects of acute binge drinking in healthy adults on serum endotoxin levels. We found that acute alcohol binge resulted in a rapid increase in serum endotoxin and 16S rDNA, a marker of bacterial translocation from the gut. Compared to men, women had higher blood alcohol and circulating endotoxin levels. In addition, alcohol binge caused a prolonged increase in acute phase protein levels in the systemic circulation. The biological significance of the in vivo endotoxin elevation was underscored by increased levels of inflammatory cytokines, TNFα and IL-6, and chemokine, MCP-1, measured in total blood after in vitro lipopolysaccharide stimulation. Our findings indicate that even a single alcohol binge results in increased serum endotoxin levels likely due to translocation of gut bacterial products and disturbs innate immune responses that can contribute to the deleterious effects of binge drinking.     

Both acute and chronic buspirone treatments have different effects on regional 5-HT synthesis in Flinders Sensitive Line rats (a rat model of depression) than in control rats

The main objective of this investigation was to evaluate the effects of buspirone, a 5-HT_1A agonist with some partial agonist properties and also an antidepressant, on regional 5-HT synthesis in Flinders Sensitive Line (FSL) rats (“depressed”), and to compare the effects to the Flinders Resistant Line (FRL) control rats (not “depressed”). In addition results were compared to those previously reported in normal Sprague–Dawley (SPD) rats (normal control). Serotonin synthesis in both FSL and FRL rats was measured following acute and chronic treatments with buspirone. Both of these strains were derived from the SPD rats. No direct comparison was done between the FSL saline and FRL saline groups, or the FSL buspirone and FRL buspirone groups, because the objective of the studies was to evaluate effects of buspirone in these two strains. The results show that acute treatment with buspirone elevates 5-HT synthesis throughout the brain in the FRL rats. In the FSL rats, there were reductions in some brain regions (e.g., dorsal and median raphe, amygdala, anterior olfactory nucleus, substantia nigra reticulate), while in other regions, there were increases in the synthesis observed (e.g., frontal, parietal, visual and somatosensory cortices, ventral hippocampus). In 20 out of the 30 brain regions investigated in the FSL rats, there was no significant change in the synthesis following acute buspirone treatment. During the chronic treatment, buspirone produced a significant reduction of 5-HT synthesis in 15 out of 30 brain regions in the FRL rats. In the FSL rats, buspirone produced a significant elevation of the synthesis in 10 out of 30 brain regions. In both the FSL and FRL rats, buspirone produced rather different effects than those reported previously for SPD (normal) rats. The acute effect in the FSL rats was somewhat similar to the effect reported previously for the SPD rats, while in the FRL rats, the acute buspirone treatment produced an effect observed previously in treatments with 5-HT_1A antagonists suggesting an action of buspirone as partial agonist in FRL rats. The data suggest that with respect to 5-HT synthesis, FRL rats differ from SPD rats (a natural control; normal rats) and, as such, indicate that when the effects related to the serotonergic system (e.g., influence of serotonergic drugs) are studied in the FSL rats and compared to those in the FRL rats, any conclusions drawn may not reflect differences relative to a normal rat.     

Effect of leukocytic endogenous mediator on C-reactive protein in rabbits.

Elevation in the plasma levels of the acute phase proteins--C-reactive protein (C-RP) and fibrinogen--were found after injection of leukocytic endogenous mediator (LEM) into rabbits. C-RP in the plasma was elevated 8 hr after injection of LEM, and maximum elevation occurred 24 hr after injection. Injection of LEM into rabbits also produced alterations in body temperature, in levels of plasma iron and zinc, and in the number of neutrophils in the peripheral blood.     

Endotoxin-like effects in acute phase response to Trypanosoma brucei brucei infection are not due to gastrointestinal leakage

Trypanosomosis is mainly an immunological and inflammatory response mediated by increased levels of pro-inflammatory cytokines. Evidence suggests that pathological changes produced during infection with trypanosomes could be initiated by nonspecific endotoxin-like substances in trypanosomes and/or Gram-negative secondary bacterial infection. Studies in trypanosome-infected rats indicate damage to the gastrointestinal tract (GIT) accompanied by increased leakage of the GIT mucosa. The current study was carried out to determine the in vivo response to endotoxin-like substances of Trypanosoma brucei brucei. To this purpose we neutralized the entrance of endotoxin through the GIT using polymyxin-B treatment and monitored the plasma concentration of the acute phase proteins SAP and Hp. The results in this study, where infection was performed in the presence of oral antibiotic that is not absorbed from GIT and which binds to and inactivates endotoxin, show that the elevated plasma levels of endotoxin-like activity and the resulting acute phase response indicated by an increase in levels of Hp and SAP, are due to trypanosome infection. Results obtained in the present study indicate that GIT is not the major source of elevated plasma endotoxin-like activity levels and the observed acute phase response was due to an increase in the levels of acute phase proteins SAP and haptoglobin.Therefore trypanosomes are responsible for the elevated plasma endotoxin-like activity levels and the subsequent systemic acute phase response in the host.     

INHIBITORY AND ANTI-INHIBITORY FACTORS OF RAT SERUM ACTIVE ON THE G1-S TRANSITION OF HEPATOCYTE CELL CYCLE

Rat hepatocytes are responsive to a serum factor inhibiting their progression through the cell cycle from the late G₁ phase to the S phase. After fractionation of normal adult rat serum by two chromatographic steps on DEAE cellulose and sephadex gel filtration, the inhibitory activity was linked to proteins having a high electronegative charge and of apparent high molecular weight. Polyacrylamide gel electrophoretic analysis of active fraction showed that the α₁ macroglobulin was its main component. Male and female baby rats were sensitive to the inhibitory factor from normal rats. Contrary to the normal adult rat serum the whole hepatectomized adult rat serum did not exhibit any inhibitory activity on the G₁-S transition. However, two components having antagonist activities: an α₁ globulin and a γ globulin, were separated by chromatographic procedures from hepatectomized rat serum.

• a. The α₁ globulin showed an inhibitory activity. It had an apparent molecular weight lower than that found in normal rats. Its activity was sex related: only male baby rats were responsive.
• b. The factor present in the γ globulin fraction was found to be antagonistic to the α₁ globulin factor. Its occurrence after hepatectomy explains the absence of inhibitory activity in the serum of hepatectomized rats.

     

Effects of acute CS2 intoxication on protein metabolism in rat brain

The effect of acute CS₂ exposure on the rat brain protein metabolism was studied with control and phenobarbitone pretreated adult male rats 1, 4 and 46 h after exposure. Increased activity of acid proteinase was detected in both test groups 1 and 4 h after exposure and it was accompanied by changes in ¹⁴C-labelled leucine turnover as well as in RNA content. The changes were more conspicuous in cerebellum than in brain in both test groups while phenobarbitone pretreatment modified the brain response towards intoxication. This modification probably represents inherent effects of barbiturate on brain protein metabolism as well as altered metabolism of CS₂.The activities of creatine kinase and nonspecific cholinesterase displayed only subtle changes as assayed in cerebral homogenate and serum. Thus a single acute CS₂ intoxication apparently causes definitive transient changes in brain protein metabolism; serum enzyme determinations may not reflect the magnitude of these changes.     

Macrophage prostaglandin E2 and oxidative responses to endotoxin during immunosuppression associated with anaesthesia and transfusion

The widespread use of blood transfusion in major surgical procedures has led to concern about the immunosuppressive effect of transfusion on patients with underlying malignancy. Transfusion may also suppress the host response to infection. The cellular mechanisms of transfusion-associated immunosuppression may involve macrophage prostaglandin E₂ (PGE₂) in modulating the host response to cancer and infection. We previously observed that the transfusion of blood increased PGE₂ production by unstimulated macrophages. To investigate this PGE₂ associated immunosuppression, we studied the effect of transfusion of rats using a physiological stimulus of macrophage PGE₂ production, bacterial endotoxin. In the same macrophages, we analysed intracellular oxidative activity. Both allogeneic and syngeneic blood transfusion were associated with increased PGE₂ release by macrophages. This stimulation of PGE₂ increased with duration of storage of blood. A similar effect of serum indicated that a humoral factor was involved. Endotoxin (50 ng/ml–500 μg/ml) stimulated PGE₂ production in all transfused subjects. The lowest endotoxin concentration gave proportionately the greatest stimulation. Oxidative activity was down-regulated in macrophages of transfused rats, supporting an immunosuppressive role of PGE₂ within the macrophage. An effect of surgery on the oxidative response was also detected.     

纳米锁阳对肝性脑病肠道菌群及免疫功能的调整

目的研究纳米中药锁阳对内毒素诱发肝硬化大鼠发生肝性脑病的肠道菌群与免疫功能的影响。方法肝硬化大鼠行小剂量内毒素腹腔注射造成肝性脑病模型。观察常态、纳米中药锁阳对肠道菌群,血清IL-2水平及血浆中血氨含量影响。结果肝性脑病大鼠血浆内毒素及血氨明显升高,正常对照组与模型组比较差异有显著性（P〈0．05）。常态锁阳治疗组与纳米锁阳治疗组血浆中血氨、内毒素均明显降低,肠道菌群失调症有明显改变。常态锁阳治疗组与自然恢复组比较差异有显著性（P〈0．05）,纳米中药治疗组与常态中药治疗组比较差异有显著性（P〈0．05）。结论高血氨是内毒素诱发肝性脑病发生的主要诱因。应用中药锁阳从调整微生态失调角度来治疗肝性脑病,取得较好疗效,纳米中药锁阳的效果更佳。     

Effects of fish oil supplementation on prostaglandins in normal and tumor colon tissue: modulation by the lipogenic phenotype of colon tumors

Dietary fish oils have potential for prevention of colon cancer, and yet the mechanisms of action in normal and tumor colon tissues are not well defined. Here we evaluated the impact of the colonic fatty acid milieu on the formation of prostaglandins and other eicosanoids. Distal tumors in rats were chemically induced to model inflammatory colonic carcinogenesis. After 21 weeks of feeding with either a fish oil diet containing an eicosapentaenoic acid/ω-6 fatty acid ratio of 0.4 or a Western fat diet, the relationships between colon fatty acids and prostaglandin E₂ (PGE₂) concentrations were evaluated. PGE₂ is a key proinflammatory mediator in the colon tightly linked with the initiation and progression of colon cancer. The fish oil vs. the Western fat diet resulted in reduced total fatty acid concentrations in serum but not in colon. In the colon, the effects of the fish oil on fatty acids differed in normal and tumor tissue. There were distinct lipodomic patterns consistent with a lipogenic phenotype in tumors. In tumor tissue, the eicosapentaenoic acid/arachidonic acid ratio, cyclooxygenase-2 expression and the mole percent of saturated fatty acids were significant predictors of inter-animal variability in colon PGE₂ after accounting for diet. In normal tissues from either control rats or carcinogen-treated rats, only diet was a significant predictor of colon PGE₂. These results show that the fatty acid milieu can modulate the efficacy of dietary fish oils for colon cancer prevention, and this could extend to other preventive agents that function by reducing inflammatory stress.     

Immunological response of the rat to infection with Taenia taeniaeformis: protective antibody response to implanted parasites.

Intraperitoneally implanted metacestodes of either T. taeniaeformis or T. crassiceps in rats provoked a high degree of resistance to oral challenge with eggs of T. taeniaeformis. This resistance was passively transferred to normal recipients with serum. Immunoglobulin fractions of immune serum containing IgG₁ or IgM were most effective in passive transfer and little activity was associated with IgG₂ antibodies. No skin-sensitizing antibodies were detectable in immune sera. These findings are in sharp contrast to previous observations involving protective immunoglobulins and reaginic antibodies in serum from rats with hepatic cysticerci of T. taeniaeformis. Possible reasons for this are discussed. Cysticerci implanted into normal rats survived for at least 21 days with no sign of host rejection, whereas those implanted into rats with hepatic infections with T. taeniaeformis were killed and encapsulated. Similar results were obtained by implanting cysticerci in normal rats given inoculations of complete Freund's adjuvant. Repeated inoculations of immune serum had no effect on the survival of implanted cysticerci, and it was concluded that exposure to infection by oncospheres provokes cellular defense mechanisms which can be effective against cysticerci in abnormal sites. Why these mechanisms are inoperative against hepatic cysticerci remains unclear.     

不同营养支持对急性重症胰腺炎的效果对比及对血清钙离子、hs-CRP、AMS、PCT的影响

摘要 目的：探讨不同营养支持对急性重症胰腺炎的效果对比及对血清钙离子、超敏C反应蛋白（hs-CRP）、淀粉酶（AMS）、降钙素原（PCT）的影响。方法：选择2015年1月到2020年12月在我院接受治疗的131例急性重症胰腺炎患者,采用随机数表法分为试验组（n=66）和对照组（n=65）。对照组给予肠外营养支持治疗,试验组给予肠内营养支持治疗。比较两组临床疗效、钙离子、hs-CRP、AMS、PCT、D-乳酸、二胺氧化酶（DAO）、内毒素、临床症状改善情况及不良反应发生情况。结果：治疗后,两组总有效率比较差异显著（P<0.05）;治疗前,试验组和对照组血清抑钙离子、hs-CRP、AMS、PCT比较无显著差异;治疗后,试验组和对照组血清hs-CRP、AMS、PCT随着时间的推移而降低,且试验组均低于对照组,血清钙离子随着时间的推移而升高,且试验组高于对照组,差异显著（P<0.05）;治疗前,试验组和对照组血清D-乳酸、DAO、内毒素比较无显著差异;治疗后试验组和对照组血清D-乳酸、DAO、内毒素随着时间的推移而降低,且试验组均低于对照组,差异显著（P<0.05）;试验组腹痛缓解、肠鸣音恢复、血淀粉酶恢复及尿淀粉酶恢复时间均显著低于对照组,差异显著（P<0.05）;两组不良反应总发生率分别为9.09%、15.38%（P>0.05）。结论：在急性重症胰腺炎患者中应用肠内营养支持效果显著,可有效改善血清钙离子、hs-CRP、AMS、PCT水平,且不良反应较低。     

High serum IL-6 level reflects susceptible status of the host to endotoxin and IL-1/tumor necrosis factor.

Patients with high level of serum endotoxin did not necessarily develop into lethal shock, whereas some patients died of septic shock even when their serum endotoxin levels were low. These results indicate that limiting factor which determines the host to be endotoxin shock principally depends on the host susceptibility to endotoxin instead of serum endotoxin level. To understand this susceptible status of the host to endotoxin, we used Propionibacterium acnes primed mouse endotoxin shock model. We found that P. acnes-primed mice responded to low dose of LPS by enhanced production of IL-1 and TNF. And such mice were highly susceptible to the lethal shock inducing effect of IL-1 and/or TNF, which also induced high level of serum IL-6 in these mice. Therefore, measurement of serum IL-6 level provides us with the information of the preceding exposure of the host to either LPS or IL-1 and/or TNF and the highly susceptible status of the host to these stimuli. Based on these results obtained from animal model, we investigated the relationship between serum IL-6 levels and serum endotoxin levels in the patients with malignant hematologic disorders. We found that these patients fell into two groups; an endotoxin susceptible group, equivalent to P. acnes-primed mice, showing high level of serum IL-6 with low level of serum endotoxin, and a nonendotoxin susceptible group, equivalent to P. acnes-nonprimed mice, showing low or undetectable level of serum IL-6 with high level of serum endotoxin. We propose that the measurement of serum IL-6 level in the patients positive for endotoxin is a useful tool in evaluating diagnosis and prognosis of endotoxin shock.     

Activation of lung vagal sensory receptors by circulatory endotoxin in rats

Although endotoxin is known to induce various pulmonary responses that are linked to the function of lung vagal sensory receptors, its effects on these pulmonary receptors are still not clear. This study investigated the effects of circulatory endotoxin on the afferent activity of lung vagal sensory receptors in rats. We recorded afferent activity arising from vagal pulmonary C fibers (CFs), rapidly adapting receptors (RARs), tonic pulmonary stretch receptors (T-PSRs), and phasic pulmonary stretch receptors (P-PSRs) in 64 anesthetized, paralyzed, and artificially ventilated rats. Intravenous injection of endotoxin (50 mg/kg; lipopolysaccharide) stimulated 7 of the 8 CFs, 8 of the 8 RARs, and 4 of the 8 T-PSRs studied, while having no effect on the 8 P-PSRs tested. The stimulation started 3-16 min after endotoxin injection and lasted until the end of the 90-min observation period. The evoked discharge of either CFs or RARs was not in phase with the ventilatory cycle, whereas that of T-PSRs showed a respiratory modulation. Injection of a saline vehicle caused no significant change in the discharge of these receptors. Additionally, endotoxin significantly produced an increase in total lung resistance, and decreases in dynamic lung compliance and arterial blood pressure. Our results demonstrate that a majority of lung vagal sensory receptors are activated following intravenous injection of endotoxin, and support the notion that these pulmonary receptors may function as an important afferent system during endotoxemia.     

Structural alterations in alpha1-antichymotrypsin from normal and acute phase human plasma

Human alpha₁-antichymotrypsin, isolated at pH 8.0 from both normal and acute phase plasma, has been found to have two different amino terminal sequences despite the fact that inhibitory activities are unchanged. In normal plasma over 90% of the protein has an amino terminal sequence beginning with aspartic acid and less than 10% with arginine. However, in acute rheumatoid arthritis plasma 55% of the inhibitor begins with arginine and the remainder with aspartic acid. Sequence studies indicate that a fifteen amino acid peptide fragment has been cleaved to yield the arginine protein. Human alpha₁-proteinase inhibitor also shows this heterogeneity, but the ratios do not change between normal and acute phase plasma. It may well be that the missing peptide has some biological activity manifested only in the acute phase state.     

Presence of acute phase changes in zinc, iron, and copper metabolism in turkey embryos

Acute phase changes in trace mineral metabolism were examined in turkey embryos. An endotoxin injection resulted in increased concentrations of serum copper and liver zinc and decreased concentrations of serum zinc in embryos incubated either in ovo or ex ovo. Changes in zinc and copper metabolism occurred when endotoxin either was injected intramuscularly, into the amnionic fluid, or administered onto the chorioallantoic membrane. Unlike poults, embryos did not respond to an inflammatory challenge with decreased serum iron concentrations. Acute phase changes in embryo serum zinc and copper as well as liver zinc concentrations were similar to those in poults. Increased liver zinc concentrations were associated with increased zinc in metallothionein (MT). An injection of a crude interleukin 1 preparation into embryos resulted in similar increases in hepatic zinc and MT concentrations as an endotoxin injection, suggesting a role for this cytokine in mediating the acute phase changes in embryonic zinc metabolism.     

Muscle wasting associated with endotoxemia in the rat: Modification by theβ 2-adrenoceptor agonist clenbuterol

A single injection of endotoxin (1 mg/kg, sc) in rats caused significant fever, body weight loss and reduction in gastrocnemius muscle mass, none of which was mimicked by pair-feeding. Infusion of endotoxin via osmotic minipump over five days caused transient fever and suppression of growth. Recovery of body weight was significantly enhanced by the administration of the ₂-adrenoceptor agonist clenbuterol (added to the diet at 4 mg/kg). In a separate experiment, injections of endotoxin (day 0 and day 2) caused significant reductions in body weight gain (42%), mass (9%) and protein content (13%) of gastrocnemius muscle over 3 days. Addition of clenbuterol to the diet reversed all of these effects but did not alter food intake or the febrile response to endotoxin. Clenbuterol caused large (20%) increases in the ratio of RNA to protein in muscle indicating that it may have stimulated protein synthesis. ₂-adrenoceptor agonists may therefore be of value in preventingor inhibiting muscle atrophy associated with infection or injury.     

Purification of a metallothionein-like protein from serum of mercury-treated rats using phosphorylcholine-Sepharose affinity column

A metallothionein-like protein (MLP) from the serum of mercury-treated rats was isolated while purifying an acute phase plasma protein, C-reactive protein, by its Ca2(+)-dependent affinity to phosphorylcholine (PC)-Sepharose column. The MLP was further purified by a single DEAE-Sephacel ion-exchange chromatography. The MLP is similar to mammalian hepatic Zn-metallothionein on the basis of its low molecular weight of approximately 7000, 7 g Zn atoms/molecule of MLP and an absorption maximum at 220 nm. The purity of the protein was confirmed by double immunodiffusion test against anti-MLP antiserum raised in a rabbit. Immunologically MLP was detected not only in the hepatic cytosol, serum and urine from Hg-treated rats but also in the serum and hepatic cytosol of untreated rats. Using PC-Sepharose column, MLP could not be purified from normal serum.