610 Medizin und Gesundheit
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Erscheinungsjahr
- 2006 (3) (entfernen)
Schlagworte
- Sympathikus (2)
- CC-Chemokinrezeptor 2 (CCR2) (1)
- CCR2 (1)
- Cytokine (1)
- Dexmedetomidin (1)
- Fibromyalgie (1)
- MCP-1 (1)
- Monozyten-chemotaktische Protein 1 (MCP-1) (1)
- Neuroendokrines System (1)
- PBMC (1)
Institut
α2-adrenerge Rezeptoren sind entscheidende Strukturen für den Ablauf einer physiologischen Stressreaktion. Verschiedene Ursachen sind bekannt, welche die Funktionalität/Effektivität der vorwiegend inhibitorischen α2-adrenergen Wirkung einschränken. Darunter fallen frühe und lebenszeitliche Stressbelastung, genetische Faktoren sowie pharmakologische Einflüsse. Ziel der vorliegenden Dissertation war die Identifikation und Charakterisierung von kognitiven und zentralnervös gesteuerten kardiovaskulären Parametern, welche durch α2-adrenerge Rezeptoren in besonderem Maße beeinflusst werden. Weiterhin sollte anhand pharmakologischer Modelle eine Methode entwickelt werden, um diese Beeinflussbarkeit quantitativ zu beschreiben. In einem komplexen pharmakologischen Versuchsplan wurde die Aktivität der α2-adrenergen Rezeptoren durch jeweils fünf Dosisstufen Dexmedetomidin (α2-adrenerger Agonist) und Yohimbin (α2-adrenerger Antagonist) manipuliert. In einem placebokontrollierten einfach-blinden Design wurde die Konzentrations-Wirkungs-Beziehung bzw. die Dosis-Wirkungs-Beziehung zwischen der Medikation und kognitiven sowie zentralnervös gesteuerten kardiovaskulären Parametern ermittelt. Zudem wurden die Effekte von α2-adrenergem Agonismus und Antagonismus auf die akustische Startlereaktion sowie auf die Plasmakonzentration von Noradrenalin (NA) und DHPG erfasst. Mittels linearer pharmakodynamischer Modellierung sollte anschließend die maximale Spannweite der α2-adrenerg vermittelten Effekte vorhergesagt werden, um so Aussagen über die pharmakologische Beeinflussbarkeit der Rezeptoren treffen zu können. Es zeigten sich deutliche Effekte von α2-adrenergem Agonismus und Antagonismus auf einfache Reaktionszeiten und kardiovaskuläre Parameter. Insbesondere sympathisch vermittelte Funktionen waren durch die pharmakologische Manipulation beeinflusst, ebenso wie die Magnitude der Blinzelreaktion auf einen akustischen Schreckreiz. Die Substanzen hatten zudem deutliche Einflüsse auf die Plasmakonzentration von NA und DHPG. Der besondere Erfolg dieser Arbeit liegt in der systematischen Quantifizierung der pharmakologischen Beeinflussung zentralnervöser Parameter durch α2-adrenergen Agonismus und Antagonismus. Es konnte gezeigt werden, dass die pharmakodynamische Modellierbarkeit zentralnervöser Parameter Aufschluss über potenzielle Gruppen-unterschiede in der Funktionalität/Effektivität α2-adrenerger Mechanismen geben kann.
Fibromyalgia is a disorder of unknown etiology characterized by widespread, chronic musculoskeletal pain of at least three month duration and pressure hyperalgesia at specific tender points on clinical examination. The disorder is accompanied by a multitude of additional symptoms such as fatigue, sleep disturbances, morning stiffness, depression, and anxiety. In terms of biological disturbances, low cortisol concentrations have been repeatedly observed in blood and urine samples of fibromyalgia patients, both under basal and stress-induced conditions. The aim of this dissertation was to investigate the presence of low cortisol concentrations (hypocortisolism) and potential accompanying alterations on sympathetic and immunological levels in female fibromyalgia patients. Beside the expected hypocortisolism, a higher norepinephrine secretion and lower natural killer cell levels were found in the patient group compared to a control group consisting of healthy, age-matched women. In addition, an increased activity of some pro-inflammatory markers was observed thus leading to alterations in the balance of pro-/anti-inflammatory activity. The results underline the relevance of simultaneous investigations of interacting bodily systems for a better understanding of underlying biological mechanisms in stress-related disorders.
The allergic contact dermatitis (ACD) to small molecular weight compounds is a common inflammatory skin reaction. ACD is restricted to industrialized countries, has an enormous sociomedical and socioeconomic impact. About 2,800 compounds from the six million chemicals known in our environment are believed to have allergic, and to a lesser degree also contact-sensitizing or immunogenic properties causing allergic contact dermatitis. ACD results from T cell responses to harmless, low molecular weight chemicals (haptens) applied to the skin. Haptens are not directly recognized by the cells of the immune system. They need to be presented by subsets of antigen presenting cells to the cells of the immune system. In this regard, epidermal Langerhans cells (LC) and the cells into which they mature (dendritic cells) are believed to play a pivotal role in the sensitization process for ACD. LC are able to bind the haptens, internalize them, and present them to naive T cells and induce thereby the development of effector T cells. They are so-called professional antigen presenting cells. This process is initiated and maintained by the release of several mediators, which are released by various cells after their contact with the haptens. One of the first proteins secreted into the environment is interleukin (IL)-1ß. This cytokine is produced and secreted minutes after an antigen enters the cell. It is commonly believed that the large amounts of this protein and other cytokines such as granulocyte-colony stimulation factor (GM-CSF) and tumor necrosis factor alpha (TNF-ï¡) needed for the initiation and activation of ACD are coming first from other cells residing in the skin, e.g., keratinocytes, monocytes and macrophages. These cytokines provide the danger signals needed for the activation of the Langerhans cell (LC), which then produce via a positive feedback loop various cytokines themselves. In addition, other proteins such as chemokines influence the generation of danger signals, migration, homing of T cells in the local lymph nodes as well as the recruitment of T cells into the skin. Thus, a small molecular compounds or hapten needs to be able to induce danger signals in order to become immunogenic. In this study, we investigated whether para-phenylenediamine (PPD), an arylamine and common contact allergen, is able to induce danger signals and likely provide the signals needed for an initiation of an immune response[162, 163]. PPD is used as an antioxidant, an ingredient of hair dyes, intermediate of dyestuff, and PPD is found in chemicals used for photographic processing. But up to date, it has not been clearly demonstrated if PPD itself is a sensitizing agent. Thus, this study aimed on the potential of PPD to provide the danger signals by studying IL-1β, TNF-ï¡, and monocyte chemoattractant proteins (MCP-1) in human monocytes, peripheral blood mononuclear cells (PBMC) from healthy volunteers, and also in two human monocyte cell lines namely U937, and THP-1. This study found that PPD decreased dose- and time-dependently the expression and release of three relevant mediators involved in the generation of danger signals. Namely, PPD reduced the mRNA and protein levels for IL-1ß, TNF-ï¡, and MCP-1 in primary human monocytes from various donors. These findings were extended and validated by investigations using the cell line U937. The data were highly specific for PPD, and no such results were gained for its known auto oxidation product called Bandrowski- base or for meta-phenylenediamine (MPD), and ortho-phenylenediamine (OPD). Therefore, we can speculate that this effect is likely to be dependent on the para-substitution. Based on these results we conclude that PPD itself is not able to mount a cascade for the induction of danger signals. It should be mentioned that it is still possible that PPD induces danger signals for sensitization by other unknown processes. Therefore, more research is still needed focusing on this subject especially in professional antigen presenting cells in order to solve the still open question whether PPD itself sensitizes naive T cells or if PPD is solely an allergen. Independently we found unexpectedly that PPD as well as other haptens such as 2, 4-Dinitrochlorobenzene, nickelsulfate, as well as some terpenoide increased clearly the expression of CC chemokin receptor 2 (CCR2), the receptor for the chemokine MCP-1. Up to date, the main importance for the CCR2 receptor comes from results demonstrating that CCR2 is critical for the migration of monocytes after encounter with bacterial lipopolysaccharides. Under these circumstances the receptor disappears from the cell surface and is down regulated. An up regulation of CCR2 has not been reported for haptens, and deserves further investigations.