Biomedical subjects

Joachim Roth

Publications and source records attributed to Joachim Roth.

5 recordsLinked to original sources

PubMed2002

Interactions of temperature and angiotensin II in paraventricular neurons of rats in vitro.

We recorded extracellular impulse activity of hypothalamic paraventricular neurons ( n=75) in rat brain slices during application of angiotensin II (ANG II, 10(-9)-10(-6) M) and/or temperature changes (32-42 degrees C). ANG II, with a threshold concentration of 10(-8) M, increased the firing rate in more than 80% of the neurons with strongest excitations occurring in bursting neurons. Increasing the temperature also raised the discharge rate in the majority of the neurons, often together with enhanced burst discharges. When ANG II was applied during ongoing sinusoidal temperature changes, its effects were more pronounced at elevated temperatures. These electrophysiological data illustrate that stimulus-encoding properties at the neuronal level can contribute to the interactions between osmoregulatory and thermoregulatory mechanisms including mutual sensitization when different stimuli (here: ANG II and temperature changes) are applied simultaneously.

Angiotensin II↗

PubMed2002

[Fever in acute illness: beneficial or harmful?].

Fever has had a long phylogenetic history: it occurs not only in infected birds and mammals, but also in infected reptiles, amphibians, fish and even insects. When these "cold-blooded" animals are prevented from adapting their body temperature to the risen thermoregulatory set-point by behavioral means, a more severe state of disease and a higher mortality are the consequences. It seems unlikely that an energy-dependent process, such as fever, would have been retained for hundreds of millions of years, in so many groups of organisms, if it provided no selective advantage. Fever may represent a leukocyte-based amplification mechanism to affect host challenge: enhanced motility of leukocytes, enhanced lymphocyte response to mitogens, increased production of interferon, enhanced immune response to viral antigens. Evidence for a beneficial effect of fever is also supported by the results of our animal experiments. Intraperitoneal injection of a high dose of bacterial lipopolysaccharide (LPS) in rats induces a septic shock like state which is accompanied by hypothermia on the day of LPS-administration and a robust fever on the following days. Co-injection of a neutralizing synthetic form of the soluble tumor necrosis factor (TNF) type 1 receptor completely neutralizes LPS-induced bioactive TNF in the lavage of the abdominal cavity and in blood plasma. Treatment with the TNF-antagonist results in much faster recovery from the hypothermic state. The rats develop pronounced fever already on the day of injection and there is significantly less reduction in body weight and food and water intake. Similar, but less pronounced effects can be induced by treatment with inhibitors of the inducible form of nitric oxide (NO)-synthase indicating that TNF-induced detrimental effects are, in part, mediated by excessive formation of NO. These results confirm that an accelerated onset of fever or a faster recovery from hypothermia in a septic state may have rather beneficial than maladaptive effects.

Animals↗

PubMed2002

Selected contribution: role of IL-6 in LPS-induced nuclear STAT3 translocation in sensory circumventricular organs during fever in rats.

Interleukin-6 (IL-6) is regarded as an endogenous mediator of lipopolysaccharide (LPS)-induced fever. IL-6 is thought to act on the brain at sites that lack a blood-brain barrier, the circumventricular organs (CVOs). Cells that are activated by IL-6 respond with nuclear translocation of the signal transducer and activator of transcription 3 molecule (STAT3) and can be detected by immunohistochemistry. We investigated whether the LPS-induced release of IL-6 into the systemic circulation was accompanied by a nuclear STAT3 translocation within the sensory CVOs. Treatment with LPS (100 microg/kg) led to a slight (1 h) and then a strong increase (2-8 h) in plasma IL-6 levels, which started to decline at the end of the febrile response. Administration of both pyrogens LPS and IL-6 (45 microg/kg) induced a febrile response with IL-6, causing a rather moderate fever compared with the LPS-induced fever. Nuclear STAT3 translocation in response to LPS was observed within the vascular organ of the lamina terminalis (OVLT) and the subfornical organ (SFO) 2 h after LPS treatment. To investigate whether this effect was mediated by IL-6, the cytokine itself was systemically applied and indeed an identical pattern of nuclear STAT3 translocation was observed. However, nuclear STAT3 translocation already occurred 1 h after IL-6 application and proved to be less effective compared with LPS treatment when analyzing OVLT and SFO cell numbers that showed nuclear STAT3 immunoreactivity after the respective pyrogen treatment. Our observations represent the first molecular evidence for an IL-6-induced STAT3-mediated genomic activation of OVLT and SFO cells and support the proposed role of these brain areas as sensory structures for humoral signals created by the activated immune system and resulting in the generation of fever.

Animals↗

PubMed2001

Influence of systemic treatment with cyclooxygenase inhibitors on lipopolysaccharide-induced fever and circulating levels of cytokines and cortisol in guinea-pigs.

Peripheral inflammatory stimuli result in the modification of a number of vital brain-controlled functions including the thermoregulatory set-point (induction of fever) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. We addressed the question of whether both of these components of the acute-phase response are induced by a common signal pathway. For this purpose we recorded body temperature (by remote radio-telemetry), HPA axis activity (circulating concentrations of cortisol by radio-immunoassay) and levels of the pro-inflammatory cytokines tumour necrosis factor and interleukin-6 (TNF, IL-6, using specific bioassays) in six groups of guinea-pigs. The animals received intra-arterial injections of either 10 microg/kg lipopolysaccharide (LPS) plus saline, 10 microg/kg LPS plus 5 mg/kg meloxicam (an inhibitor of the inducible form of cyclooxygenase), 10 microg/kg LPS plus 5 mg/kg diclofenac (a non-selective cyclooxygenase inhibitor), saline plus solvent, saline plus 5 mg/kg meloxicam or saline plus 5 mg/kg diclofenac. Injection of the cyclooxygenase inhibitors per se had no influence on the investigated parameters. Injection of LPS alone resulted in a biphasic fever, a more than fivefold increase in circulating cortisol and pronounced induction of TNF and IL-6. Treatment with the cyclooxygenase inhibitors either attenuated (meloxicam) or abolished (diclofenac) LPS-induced fever, but had no effect on the LPS-induced rise of plasma cortisol or IL-6. Circulating levels of TNF, in response to LPS, were enhanced by meloxicam and diclofenac, reflecting the negative feedback control exerted by prostaglandins on cytokine (specifically TNF) formation. These results provide the first evidence that the prostaglandin-dependent inflammatory pathway for fever induction is distinct from the pathway of HPA axis activation since fever, but not circulating cortisol, was attenuated by an inhibition of prostaglandin formation.

Animals↗

PubMed1998

Tolerance to pyrogens.

In humans or experimental animals, the repeated confrontation with lipopolysaccharides (LPS) from gram-negative bacteria, but not with muramyl dipeptide (MDP) from gram-positive bacteria, leads to attenuation of almost all pathophysiologic effects mediated by proinflammatory cytokines. Our experiments in guinea pigs and rats demonstrate that attenuation of the febrile response during the development of LPS tolerance is associated with a reduced production of cytokines rather than a decrease in responsiveness to cytokines. Cross-tolerance experiments demonstrate that different stimuli influencing LPS-induced tumor necrosis factor (TNF) release and nitric oxide (NO) synthesis can modify the development of tolerance. On the other hand, the lack of cross-tolerance between LPS and MDP indicates that MDP can activate the cytokine cascade and induce the febrile response in animals tolerant to LPS. This may indicate distinct receptors and signal pathways for LPS and MDP, leading to activation of the cytokine cascade. LPS tolerance has also been demonstrated in ex vivo and in vitro studies. In cultures of monocytes, diminished synthesis of TNF and NO reported after LPS restimulation could be prevented and reversed by interferon and granulocyte-macrophage colony-stimulating factor. These findings add an additional hypothesis in tolerance development.

Acetylmuramyl-Alanyl-Isoglutamine↗