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Wirkmechanismen nasaler Glukokortikosteroide in der Therapie der allergischen Rhinitis

Teil 1: Pathophysiologie, molekulare Grundlagen

Mechanism of action of nasal glucocorticosteroids in the treatment of allergic rhinitis

Part 1: Pathophysiology, molecular basis

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Zusammenfassung

Die allergische Rhinitis ist eine häufige Atemwegserkrankung, die durch eine Hyperreaktivität der Schleimhaut, erhöhte Sekretion und Entzündungsprozesse sowie einen hiermit einhergehenden Gewebsumbau („remodelling“) charakterisiert ist. Die Gabe antiallergischer und antiinflammatorischer Medikamente wie nasaler Glukokortikosteroide (nGCS) stellt hierbei die wichtigste Therapiemaßnahme dar.

nGCS üben über mindestens zwei verschiedene Mechanismen einen antiinflammatorischen Effekt aus: zum einen durch Transaktivierung, zum anderen durch Transrepression. Darüber hinaus wird GCS eine regulatorische Funktion zugeschrieben, indem sie regulatorische Zytokine und Forkhead Box P3 (Foxp3) induzieren. Foxp3 ist ein wichtiger Transkriptionsfaktor regulatorischer T-Zellen, der es ermöglicht, andere CD4 +- Zellen in ihrer Effektorfunktion und Proliferation zu inhibieren.

Das Wissen über die Kenntnisse der molekularen Mechanismen erlaubt heute, die antiinflammatorischen Wirkung von nGCS gezielter und frühzeitiger zu nutzen.

Abstract

Allergic rhinitis (AR) is a common airway disease characterized by mucosal swelling leading to congestion, mucosal hyperreactivity and increased secretions. Inflammatory processes in the mucosa are responsible for most symptoms and are characterized by mucosal remodeling after longer time periods.

The early phase response, which is characterized by sneezing, rhinorrhea and nasal congestion, is the response of the sensory nerve terminals and blood vessels in the nasal mucosa to chemical mediators such as histamine, prostaglandins and leukotrienes. Nasal exposure to allergens leads to infiltration of inflammatory cells, such as activated eosinophils and T helper type 2 (TH2) cells, into the nasal mucosa by chemoattractant factors such as cytokines including interleukin 5 (IL-5), chemical mediators including cysLTs and chemokines including eotaxin. Edema of the nasal mucosa develops as a secondary reaction with inflammatory cells. This inflammation, referred to as the late-phase response, develops 6–10 h after allergen challenge and causes prolonged nasal congestion. In addition, a neurogenic mechanism is activated after liberation of substance P and others. Therefore, allergic rhinitis is a complex immunogenic disease that also activates mechanisms of the immune system in general. Antiallergic and antiinflammatory medications such as nasal glucocorticosteroids (nGCS) are thought to be the most effective treatment for controlling the symptoms and inflammatory mechanisms of AR.

The antiinflammatory action of nGCS depends on at least two different mechanisms: transactivation and transrepression. Moreover, they regulate immune functions by inducing regulatory cytokines and forkhead box P3 (Foxp3). Foxp3 is of upmost importance as a transcription factor of regulatory t-cells, allowing the inhibition of effector function and proliferation of other CD4 + cells.

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Abbreviations

APZ:

antigenpräsentierende Zellen

AP-1:

„activator protein-1“

AR:

allergische Rhinitis

BALF:

bronchoalveoläre Lavageflüssigkeit

bFGF:

“basic fibroblast growth factor”

cysLT:

Cysteinyl-Leukotriene

CD:

“cluster of differentiation”

cDNA:

„complementary“ Desoxyribonukleinsäure

DC:

dendritische Zelle

ECP:

eosinophiles kationisches Protein

EIA:

Enzymimmunoassay

FcεRI:

hochaffine IgE-Rezeptoren

Foxp3:

Forkhead Box P3

GILZ:

“glucosteroid-induced-leucine zipper”

GM-CSF:

“granulocyte macrophage colony-stimulating factor”

GR:

Glukokortikoidrezeptor

H1-Rezeptor:

Histaminrezeptor vom Typ 1

ICAM-1:

interzelluläres Adhäsionsmolekül 1

IFN:

Interferon

IgE:

Immunglobulin E

IL:

Interleukin

LT:

Leukotriene

MHC:

“major histocompatibility complex”

mRNA:

Messenger-Ribonukleinsäure

NFκB:

“nuclear factor kappa B”

nGCS:

nasale Glukokortikosteroide

NGF:

“nerval growth factor”

NO:

Stickstoffmonoxid

PAF:

plättchenaktivierender Faktor

PG:

Prostaglandin

TARC:

“thymus and activation regulated chemokine”

TGF:

“transforming growth factor”

TH1 :

T-Helferzellen vom Typ 1

TH2 :

T-Helferzellen vom Typ 2

TLR-Rezeptor:

Toll-like-Rezeptor

TNF-α:

Tumornekrosefaktor-α

TOVAs:

“test of variables of attention”

TXA2:

Thromboxan A2

Treg-Zellen:

T-regulatorische Zellen (Lymphozyten)

VCAM:

“vascular cell adhesion molecule”

VEGF:

“vascular endothelial growth factor”

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Der korrespondierende Autor weist auf folgende Beziehungen hin: Der korrespondierende Autor erhielt Unterstützung für wissenschaftliche Forschungsprojekte/Vortragshonorare/Beratung von folgenden Firmen: ALK-Abello, Dänemark; Allergopharma, Deutschland; Artu Biologicals, Niederlande; Bencard, Großbritannien; Bionorica, Deutschland; Boehringer Ingelheim, Deutschland; Curalogic, Dänemark; Cytos, Schweiz; GSK, Großbritannien; HAL, Niederlande; Hartington, Spanien; Leti, Spanien; Lofarma, Italien; MSD, USA; Novartis, Schweiz; Optima, Deutschland; Phadia/Thermofisher, Schweden; Roxall, Deutschland.

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  1. Zentrum für Rhinologie und Allergologie, An den Quellen 10, 65183, Wiesbaden, Deutschland

    L. Klimek & O. Pfaar

  2. Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität, Würzburg, Deutschland

    P. Högger

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  1. L. Klimek
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Klimek, L., Högger, P. & Pfaar, O. Wirkmechanismen nasaler Glukokortikosteroide in der Therapie der allergischen Rhinitis. HNO 60, 611–617 (2012). https://doi.org/10.1007/s00106-012-2483-4

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