Endotoxin-induced Fever Research Articles

Study on the antipyretic mechanism of large pushing Tianheshui for young rabbits with endotoxin-induced fever

ObjectiveTo observe the effect of large pushing Tianheshui manipulation intervention on the body temperature of young rabbits with endotoxin-induced fever and discuss its antipyretic mechanism.MethodsThirty-two young rabbits meeting the standards were selected from 40 ordinary young male New Zealand rabbits after being adapted for 7 d, and randomly divided into a normal group, a model group, a large pushing Tianheshui group, and an ibuprofen group according to the random number table method, with 8 rabbits in each group. Rabbits in the model group, the large pushing Tianheshui group, and the ibuprofen group were subjected to preparing the endotoxin-induced fever model by intravenous lipopolysaccharide from the marginal ear vein. Rabbits in the large pushing Tianheshui group received Tuina (Chinese therapeutic massage) manipulation intervention 1.5 h and 2.5 h after modeling, respectively. Rabbits in the ibuprofen group were intragastrically given ibuprofen suspension 1.5 h after modeling. The dynamic changes in body temperature were observed for the young rabbits after fever modeling. Enzyme-linked immunosorbent assay was used to determine the content changes in positive mediators of hypothalamic body temperature, including prostaglandin (PG) E2 and cyclic adenosine monophosphate (cAMP), as well as negative mediators of hypothalamic body temperature, including arginine vasopressin (AVP) and α-melanocyte stimulating hormone (α-MSH).ResultsThe body temperature of the young rabbits in the model group was significantly higher than that in the normal group at 0.5–4.0 h, 5.0 h, and 5.5 h after modeling (P<0.01), showing two obvious fever peaks in the model group at 1.5 h and 3.0 h after modeling, respectively, with the highest peak at 1.5 h. Compared with the model group, body temperatures of the large pushing Tianheshui group and the ibuprofen group decreased significantly after 0.5 h of intervention (P<0.05). Compared with the normal group, the contents of PGE2 and cAMP were significantly increased (P<0.05), and the contents of AVP and α-MSH were significantly decreased (P<0.01) in the hypothalamus of the model group. Compared with the model group, the contents of PGE2 and cAMP were significantly decreased (P<0.01), and the levels of AVP and a-MSH were significantly increased (P<0.01) in the hypothalamus in the large pushing Tianheshui group and the ibuprofen group. There were no significant differences in the PGE2, cAMP, AVP, and α-MSH contents in the hypothalamus between the ibuprofen group and the large pushing Tianheshui group (P>0.05).ConclusionLarge pushing Tianheshui manipulation has a significant antipyretic effect on endotoxin-induced fever in young rabbits. The mechanism may be related to inhibiting the positive regulators (PGE2 and cAMP) and promoting the negative regulators (AVP and α-MSH) of hypothalamic control of body temperature.

Dietary L-citrulline influences body temperature and inflammatory responses during nitric oxide synthase inhibition and endotoxin challenge in chickens

Recent studies have revealed the role of L-citrulline (L-CIT) in thermoregulation, but very little is known about the mechanisms involved. In this study, nitric oxide synthase inhibition and endotoxin-induced fever were used to investigate the effects of L-CIT on body temperature and inflammatory responses. In experiment 1, NW-nitro-L-arginine methyl ester (L-NAME, 150 mg/kg BW), was i. p. injected into chicks fed with basal (CON) or L-CIT diets for 14 days. In experiment 2, Lipopolysaccharide (LPS, 2 mg/kg BW) was i. p. injected following 21d feeding with CON or L-CIT diets. In experiment 3, chickens were injected with either L-NAME, LPS, or L-NAME + LPS following 26 days feeding with CON or L-CIT diets. The rectal (RT), ear (ET), and core body temperature (CBT) of chickens were examined. Results showed that L-NAME effectively decreased the RT, ET, CBT, and plasma NO concentration. In contrast, LPS increased NO levels and initiated hyperthermia by increasing RT, ET, CBT, and PGE2 levels. L-CIT diet reduced the mean CBT in experiment 1 and diminished the NO level, PGE2 level, and mean RT in experiment 3. Co-administration of L-CIT + LPS upregulated IL-6 expression, whereas, LPS injection alone induced IL-10, IL-1β, and TLR4 gene expressions. Therefore, this study reveals that L-CIT-induced hypothermia was related to NO inhibition and a decrease in PGE2 concentration. Conversely, LPS induced hyperthermia was associated with an increase in both NO and PGE2 concentrations.

The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway.

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.

Efficacy of a Fixed-Dose Combination of Ibuprofen and Acetaminophen Compared With Individual Monocomponents in Adult Male Subjects With Endotoxin-Induced Fever: A Randomized Controlled Trial

PurposeThis study evaluated antipyretic efficacy and onset of a novel fixed-dose combination (FDC) of ibuprofen (IBU; 250 mg) and acetaminophen (APAP; 500 mg) compared with placebo and IBU or APAP monocomponents. MetThis single-center, randomized, double-blind, placebo-controlled, full-factorial study was conducted in healthy males aged 18 to 55 years with pyrexia induced by intravenous administration of reference standard endotoxin (RSE). After attainment of an oral temperature ≥38.1°C, subjects were randomized 3:3:3:1 to a double-blind single oral dose of FDC IBU/APAP 250 mg/500 mg, APAP 500 mg, IBU 250 mg, or placebo. Oral temperature was measured every 10 minutes for 2 hours, then every 30 minutes until 8 hours postdose. Time-weighted sum of temperature differences from baseline to 8 hours (WSTD0–8) after study medication administration was the primary efficacy end point. Secondary end points included WSTD scores from 0 to 2 hours, 0 to 4 hours, 0 to 6 hours, and 6 to 8 hours; time to return to “normal” temperature; time to rescue medication use; and global drug evaluation. Safety was assessed via adverse events (AEs). FindingsTwo hundred ninety subjects were randomized; 273 were included in the primary efficacy analysis. WSTD0–8 was significantly better for FDC IBU/APAP 250 mg/500 mg (P = 0.002), IBU 250 mg (P = 0.030), and APAP 500 mg (P = 0.023) versus placebo; there were no significant differences between active treatments. For WSTD0–2, only the FDC was statistically significant versus placebo (P = 0.004). All active treatments were significantly better (P < 0.05) for WSTD0–4 and WSTD0–6 versus placebo; there were no differences in WSTD6–8 between cohorts. Temperature returned to normal during the 8-hour treatment period in ∼50% of subjects in each cohort. Only 1 subject (IBU cohort) took rescue medication. Post hoc analyses at early time points revealed significant treatment differences favoring FDC versus placebo and IBU for the WSTD from baseline during the 50- to 110-minute posttreatment window; for WSTD from baseline during the 80- to 110-minute posttreatment window, FDC provided significant treatment differences versus placebo and both monocomponents. Overall, 223 (76.9%) of 290 subjects experienced AEs related to RSE; only 2 subjects experienced treatment-related AEs (FDC, rash; placebo, ear pain). ImplicationsAlthough the primary end point was not met, these results suggest that FDC IBU/APAP 250 mg/500 mg provides effective antipyresis with a faster onset versus equal doses of IBU and APAP alone. ClinicalTrials.gov identifier: NCT02761980.

ETA receptors are involved in the febrile response induced by high dose of bacterial endotoxin.

Previous studies have demonstrated that endothelin-1 (ET-1) is involved in the febrile response induced by lipopolysaccharide (LPS) in male and female rats. This peptide induces fever acting on ETB receptors in the central nervous system. However, during sepsis, endothelinergic ETA receptors in the brain also exert an important role reducing the mortality of the animals. The present study evaluated the participation of ETA receptors in the febrile response induced by different doses LPS in rats. Male Wistar rats were treated with the ETA receptor antagonist BQ123 before or after the injection of a low dose (10μg/kg) or a high dose (200μg/kg) of LPS intraperitoneally. The febrile response was evaluated. The treatment with BQ123, in both protocols did not change the febrile response induced by the lower dose of LPS. The pre-treatment with BQ123 also did not significantly change the febrile response induced by a higher dose of LPS but the post-treatment with the antagonist abolished the febrile response induced by this dose of LPS. These results suggest that even though ETA receptors are not recruited in the febrile response induced by lower doses of LPS, they are involved in the febrile response induced by high doses of this stimulus.

Loss of hypothermic and anti-pyretic action of paracetamol in cyclooxygenase-1 knockout mice is indicative of inhibition of cyclooxygenase-1 variant enzymes

Paracetamol (acetaminophen), is a centrally-acting antipyretic analgesic drug, which can also lower body temperature. Despite a century of clinical use, its mechanism of pharmacological action has not been completely elucidated. Previously, we demonstrated significant attenuation in the paracetamol induced hypothermia in parallel with its inhibitory action on the synthesis of brain prostaglandin E2 (PGE2) in cyclooxygenase-1 (COX-1) knockout mice in comparison to wild-type mice. The above reported pharmacological actions by paracetamol were completely retained in COX-2 knockout mice. We thus concluded that the mechanism of hypothermic action of paracetamol is dependent on inhibition of a COX-1 gene-derived enzyme. In the current investigation, we provide further support for this notion by demonstrating that the paracetamol-induced hypothermia is not mediated through inhibition of COX-1 as neither the COX-1 selective inhibitor, SC560, nor the COX-1/COX-2 dual inhibitor, indomethacin, induced hypothermia at pharmacologically active doses in mice. In addition, using a COX-2-dependent and PGE2-mediated model of endotoxin-induced fever, paracetamol induced anti-pyretic and hypothermic actions in COX-1 wild-type mice. These effects were fully or partially attenuated in COX-1 knockout mice after prophylactic or therapeutic administration, respectively. Therapeutically-administered paracetamol also reduced hypothalamic PGE2 biosynthesis in febrile COX-1 wild-type mice, but not in febrile COX-1 knockout mice. In conclusion, we provide further evidence which suggests that the hypothermic and now anti-pyretic actions of paracetamol are mediated through inhibition of a COX-1 variant enzyme.

Extract from Coriolus versicolor fungus partially prevents endotoxin tolerance development by maintaining febrile response and increasing IL-6 generation.

Endotoxin tolerance is defined as a reduced endotoxin-induced fever following repeated injections of lipopolysaccharide (LPS). Clinical examples of endotoxin tolerance include sepsis or cystic fibrosis. This state is characterized by inhibition of pro-inflammatory cytokines production and decrease in nuclear factor-kappa B (NF-κB) activation. Extract from Coriolus versicolor (CV) fungus is classified as a biological response modifier, which exhibits various biological activities, including immunopotentiating properties. The aim of study was to examine the effect of CV extract injection on body core temperature of Wistar rats during LPS-induced endotoxin tolerance. Body temperature was measured using biotelemetry. CV extract was injected intraperitoneally (100 mg kg-1) 2 h prior to the first LPS peritoneal administration (50 μg/kg). Endotoxin tolerance was induced by three consecutive daily injections of LPS at the same dose. We also investigated the influence of CV extract pre-injection on the properties of peripheral blood mononuclear cells (PBMCs) isolated from LPS-treated rats in response to LPS stimulation ex vivo. PBMCs were isolated 2 h after the first LPS injection. After 24 h pre-incubation, the cells were stimulated with LPS (1 μg ml-1) for 4 h. Our results revealed that CV extract partially prevents endotoxin tolerance through maintaining febrile response in rats following consecutive exposure to LPS. This state was accompanied by the ability of PBMCs isolated from rats injected with CV extract and LPS to release larger amounts of interleukin 6 and greater NF-κB activation in response to LPS stimulation ex vivo compared with the cells derived from rats injected only with LPS. Data also showed that CV extract augmented mitogenic effect of LPS on PBMCs and caused increase in reactive oxygen species generation. We concluded that CV extract, by a modifying effect on body temperature during endotoxin tolerance, can be consider as the immunostimulating agent, which prevents the non-specific refractoriness described in patients with sepsis or ischemia.

The neurokinin-1 receptor is involved in the mediation of endotoxin-induced fever in mice

The neurokinin-1 receptor is involved in the mediation of endotoxin-induced fever in mice

Pharmacokinetics of lincomycin following intravenousadministration in febrile goats

Disposition of antimicrobials is known to be altered during disease conditions and fever is one of the common manifestations of bacterial infections in animals. The disposition of lincomycin (10 mg/kg, IV) during Echerichia coli endotoxin-induced fever in goats followed two compartment open model and drug was detected in plasma up to 8 h. The high AUC (39.5±6.21 mg.h/mL) indicated good antibacterial activity of lincomycin in goats. The volume of distribution and total body clearance were 3.35±0.45 L/kg and 0.28±0.03 L/h/kg, respectively. The long elimination half life 9.93± 2.83 h indicated persistence of drug for longer period in body. Lincomycin, is suggested to be repeated at 24 h interval for organisms sensitive to lincomycin having MIC up to 0.6 µg/mL for the treatment of bacterial infections manifested with fever in goats.

A Randomized Study of the Efficacy and Safety of Intravenous Acetaminophen vs. Intravenous Placebo for the Treatment of Fever

This randomized, double-blind, placebo-controlled study evaluated the antipyretic effect and safety of intravenous (i.v.) acetaminophen using an endotoxin-induced fever model. Subjects exhibiting sufficient fever response following administration of reference standard endotoxin (RSE) were randomly assigned to receive i.v. acetaminophen 1,000 mg (n = 31) or matching placebo (n = 29). The primary efficacy end point was the weighted sum of temperature differences from baseline through 6 h. Relative to placebo, i.v. acetaminophen administration produced a rapid decrease in temperature that persisted throughout the 6-h study period. The primary end point favored i.v. acetaminophen over placebo (P < 0.001). Temperature differences from baseline reached statistical significance at T30 min after endotoxin administration (15 min after completing the study medication infusion). Acetaminophen administered i.v. was well tolerated, and the frequency of adverse events was comparable to that after administration of i.v. placebo. This study shows that i.v. acetaminophen in a single 1,000-mg dose is safe and effective in reducing fever.

The Effect of Fever on Quinine and Quinidine Disposition in the Rat

The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin-induced fever in rats resulted in an increased quinine clearance (CL) (4.49 +/- 1.45 vs 1.38 +/- 0.65 L h-1 kg-1, P less than 0.001) and volume of distribution (Vd) (42.6 +/- 8.8 vs 28.9 +/- 10.3 L kg-1, P less than 0.05) with a concomitant shortening of the elimination half-life (t1/2) (7.1 +/- 2.5 vs 15.9 +/- 5.9 h, P less than 0.01). With quinidine, however, fever resulted in an increased CL (3.95 +/- 1.05 vs 1.89 +/- 0.60 L h-1 kg-1, P less than 0.002) with no change in Vd and a significant decrease in t1/2 (5.1 +/- 0.7 vs 10.1 +/- 2.8 h, P less than 0.001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In-vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense.

Endotoxin-induced fever increases the clearance of methohexitone in rabbits.

We have previously observed that the clearance of methohexitone, given by continuous infusion for sedation in the intensive care unit, was influenced by body temperature in patients with post-operative fever. The aim of the present study was to reproduce this finding in an animal model that can then be used to predict similar influences for other anaesthetic agents. Sixteen rabbits were infused for 2.0 h with methohexitone (8.4 +/- 0.5 mg kg-1 h-1 (mean +/- s.d.)) and in eight of them fever was induced with intravenous Escherichia coli endotoxin. Arterial blood samples were taken over 6 h and plasma concentrations of methohexitone were assayed by gas chromatography. The mean body temperatures of the rabbits over the periods of measurement varied between 38.5 and 41.8 degrees C, and the total clearance of methohexitone (mean 50.7 mL min-1 kg-1) was positively correlated with temperature (r = 0.545, P = 0.029). No significant correlations with temperature were found for other pharmacokinetic parameters. We conclude that these observations correspond to the findings in the clinical pharmacokinetic study, showing the validity of the animal model.

A Randomized Study of the Efficacy and Safety of Intravenous Acetaminophen Compared to Oral Acetaminophen for the Treatment of Fever

The purpose of this study was to assess the safety and dynamics of the onset of antipyretic efficacy of intravenous (IV) acetaminophen versus oral (PO) acetaminophen in the treatment of endotoxin-induced fever. This randomized, double-blind, double-dummy, single-dose study was conducted at a single center in the United States in healthy volunteer adult males with an endotoxin-induced fever to assess the antipyretic efficacy and safety of IV acetaminophen 1 g versus PO acetaminophen 1 g over 6 hours. Subjects who achieved a sufficient fever response to a test dose of reference standard endotoxin were randomly assigned to receive either IV acetaminophen and PO placebo (n = 54) or PO acetaminophen and IV placebo (n = 51). The primary efficacy outcome was the weighted sum of temperature differences from baseline at time T0 through T120 minutes. Safety evaluations included adverse event (AE), physical exam, and laboratory assessments. Of 105 subjects receiving study medication, 24 vomited within 2 hours postdose (PO acetaminophen, n = 15; and IV acetaminophen, n = 9) and were excluded from the modified intent-to-treat population that consisted of 36 and 45 subjects treated with PO and IV acetaminophen, respectively. While this was done to not confer an advantage to the IV formulation, a sensitivity analysis including these subjects did not change the overall efficacy results. Statistically significant results favoring IV acetaminophen were observed for the primary endpoint (weighted sum of temperature differences over 120 minutes, p = 0.0039) and also at each time point from T30 to T90 minutes, although the maximum mean observed temperature difference was only 0.3°C. The study drugs were well tolerated. The AE frequency was comparable between the IV and PO groups. A single dose of IV acetaminophen is as safe and effective in reducing endotoxin-induced fever as PO acetaminophen. IV acetaminophen may be useful where patients are unable to tolerate PO intake or when an earlier onset of action is desirable.

Influence of experimentally induced fever on the disposition of cefpirome in buffalo calves

The influence of Escherichia coli endotoxin-induced fever on the disposition of cefpirome was investigated in five male buffalo calves following a single intravenous dose of 10 mg kg −1. Blood samples were collected from 1 min to 24 h of drug administration. The drug concentration in plasma was estimated by microbiological assay using E. coli as a test organism. The disposition of cefpirome followed two-compartment open model and the drug was detected above the minimum inhibitory concentration in plasma up to 12 h. The Vd area and AUC were 0.75 ± 0.01 L kg −1 and 35.1 ± 0.46 μg ml −1 h, respectively. The elimination half-life of 1.81 ± 0.009 h and Cl B of 0.29 ± 0.004 L kg −1 h −1 reflected rapid elimination and body clearance of cefpirome in febrile buffalo calves. Based on the results, a satisfactory dosage regimen of cefpirome in febrile buffalo calves was calculated to be 6 mg kg −1 to be repeated at 8 h intervals.

Characterization of the antinociceptive and anti-inflammatory activities of doxycycline and minocycline in different experimental models

Tetracyclines induce anti-inflammatory effects unrelated to their antimicrobial activities. We investigated the effect induced by minocycline and doxycycline in models of nociceptive and inflammatory pain, edema, fever, cell migration and formation of fibrovascular tissue, as these effects have not been fully investigated. Tetracyclines were administered via intraperitoneal route 1 h before the tests. Minocycline and doxycycline (100 mg/kg) inhibited the second phase of the formalin-induced nociceptive response in mice. Doxycycline (100 mg/kg) also inhibited the first phase. The nociceptive response induced by phorbol 12,13-didecanoate (PDD) in mice was inhibited by doxycycline (100 mg/kg). Furthermore, carrageenan-induced mechanical allodynia in rats was inhibited by doxycycline and minocycline (50 or 100 mg/kg). However, they did not enhance the latency in the hot-plate test. It is unlikely that antinociception resulted from motor incoordination or muscle relaxing effect, as both tetracyclines (100 mg/kg) did not impair the motor activity of mice in the rota-rod test. Doxycycline (50 or 100 mg/kg) or minocycline (50 or 100 mg/kg) inhibited carrageenan-induced paw edema in rats. However, only minocycline (100 mg/kg) inhibited PDD-induced edema. Carrageenan-induced leukocyte migration into the peritoneal cavity of rats was inhibited by both tetracyclines (100 mg/kg). Endotoxin-induced fever in rats was also inhibited by doxycycline (50 or 100 mg/kg) or minocycline (100 mg/kg). Finally, formation of fibrovascular tissue induced by subcutaneous implant of a cotton pellet in mice was inhibited by a 6-day administration of both tetracyclines (50 or 100 mg/kg day). Concluding, this study clearly shows the antinociceptive and anti-inflammatory activities of these second-generation tetracyclines.

Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide

Over the last three decades, experiments in several mammalian species have shown that the febrile response to bacterial endotoxin is attenuated late in pregnancy. More recent evidence has established that the expression of nitric oxide synthase (NOS) enzymes is increased in the brain late in pregnancy. The current study investigated the possible role of brain nitric oxide in mediating the phenomenon of fever suppression. Core body temperature (Tb) of near-term pregnant rats (day 19 and 20) was measured following inhibition of brain NOS and intraperitoneal injection of LPS (50 microg/kg); they were compared with both day 15 pregnant and virgin animals. Intracerebroventricular injection with an inhibitor of NOS, NG-monomethyl-L-arginine citrate (L-NMMA; 280 microg), in near-term pregnant rats restored the febrile response to LPS. As expected, near-term dams that received intracerebroventricular vehicle + IP LPS did not increase Tb, in contrast to the 1.0 +/- 0.2 degrees C rise in Tb in dams treated with ICV L-NMMA + IP LPS (P < 0.01). In virgin females and day 15 pregnant controls receiving this treatment, the increases in Tb were 1.5 +/- 0.3 degrees C and 1.6 +/- 0.4 degrees C, respectively. Thus, blockade of brain NOS restored the febrile response to LPS in near-term dams; at 5 h postinjection, Tb was 60-70% of that observed in virgins and day 15 pregnant animals. Intracerebroventricular L-NMMA alone did not induce a significant change in Tb in any group. These results suggest that the mechanism underlying the suppression of the febrile response in near-term pregnancy is mediated by nitric oxide signaling in the brain.

The mysterious role of prostaglandin E2 in the medullary raphé: a hot topic or not?

the study by tanaka and mcallen published in this issue of American Journal of Physiology–Regulatory Integrative and Comparative Physiology ([32][1]) addresses a subject of considerable interest in the field of thermoregulation and one that for many years has been central to our understanding of

110 Reduced Expression of Microsomal Prostaglandin Synthase 1 Attenuates Ventilatory Effects of Interleukin-1â in Neonatal DBA/1LACJ Mice

Background: Infection and apnea represent major medical concerns in the neonatal population, and the pro-inflammatory cytokine interleukin-1Â (IL-1Â ) may serve as a critical link between these events. We recently showed that IL-1Â depresses respiration and anoxic survival via a prostaglandin-dependent mechanism (Olsson et al, 2003). In brain, microsomal prostaglandin E synthase 1 (mPGES-1) has been demonstrated crucial for the development of endotoxin-induced fever and is widely expressed in endothelial cells of the blood-brain-barrier after IL-1Â provocation. These same cells also express the IL-1 receptor as well as cyclooxygenase-2, which catalyzes the formation of prostaglandin H2 (PGH2) from arachidonic acid. mPGES-1 subsequently synthesizes prostaglandin E2 (PGE2) from PGH2. This study tested the hypothesis that IL-1Â alters respiratory control in newborn mice via a PGE2-mediated pathway.Methods: Respiratory behavior was examined using flow plethysmography in 9 day-old DBA/1lacJ wildtype mice and heterozygote knockout mice for mPGES-1. At 70 min after an intraperitoneal injection of either IL-1Â or saline, mice were placed unrestrained in the plethysmograph chamber. Basal respiration and the ventilatory response to anoxia (100% N2) and hyperoxia (100% O2) were then examined. Genotyping was performed after experimentation in all animals.Results: During normoxia, wildtype mice given IL-1Â exhibited a reduced respiratory frequency and tidal volume compared to control animals. Heterozygote knockout mice for mPGES-1 experienced less depression of basal respiration by IL-1Â. In response to anoxia, the IL-1Â -treated wildtype mice displayed fewer gasps and were unable to sustain gasping efforts for as long as control animals. They also were less able to autoresuscitate and survive following severe hypoxic apnea compared to control animals. These deleterious effects of IL-1Â were prevented in mice with a reduced expression of mPGES-1. Skin temperature was similar between groups prior to and following experimentation, suggesting that the results observed here are not due to confounding systemic changes induced by IL-1Â.Conclusion: This study indicates that IL-1Â adversely affects respiration and autoresuscitation in newborn mice and that these changes are mediated by PGE2. These findings may have clinical implications for the screening and treatment of neonatal apnea associated with infection.

Endotoxin inhibits the surge secretion of gonadotropin-releasing hormone via a prostaglandin-independent pathway.

Immune/inflammatory challenges, such as bacterial endotoxin, disrupt gonadotropin secretion and ovarian cyclicity. We previously determined that endotoxin can block the estradiol-induced LH surge in the ewe. Here, we investigated mechanisms underlying this suppression. First, we tested the hypothesis that endotoxin blocks the estradiol-induced LH surge centrally, by preventing the GnRH surge. Artificial follicular phases were created in ovariectomized ewes, and either endotoxin or vehicle was administered together with a surge-inducing estradiol stimulus. In each ewe in which endotoxin blocked the LH surge, the GnRH surge was also blocked. Given this evidence that endotoxin blocks the estradiol-induced LH surge at the hypothalamic level, we began to assess underlying central mechanisms. Specifically, in view of the prior demonstration that prostaglandins mediate endotoxin-induced suppression of pulsatile GnRH secretion in ewes, we tested the hypothesis that prostaglandins also mediate endotoxin-induced blockade of the surge. The prostaglandin synthesis inhibitor flurbiprofen was delivered together with endotoxin and the estradiol stimulus. Although flurbiprofen abolished endotoxin-induced fever, which is a centrally generated, prostaglandin-mediated response, it failed to reverse blockade of the LH surge. Collectively, these results indicate endotoxin blocks the LH surge centrally, suppressing GnRH secretion via a mechanism not requiring prostaglandins. This contrasts with the suppressive effect of endotoxin on GnRH pulses, which requires prostaglandins as intermediates.

Anti-endotoxic effects of syringic acid ofRadix Isatidis

The anti-endotoxic effect of syringic acid (SA) isolated from Radix Isatidis (Banlangen, BLG) was studied. SA was extracted and isolated from BLG and diluted into 1% solution. The content of SA-pretreated endotoxin (ET) was quantitatively determined using Limulus test. The ability of fever induction of ET pretreated with SA was measured using endotoxin-induced fever test in rabbits. The LPS-induced death in mice pretreated with and without SA was compared. Results showed that after pretreatment with SA, 83.16% of ET was destroyed, the ET-induced fever in rabbits relieved markedly and the LPS-induced death rate in mice dropped from 68% to 20%. It was concluded that SA isolated from BLG had anti-endotoxic effects.