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Project

Impact of epithelial barrier dysfunction on inflammation in allergic rhinitis

Patients with allergic rhinitis (AR) suffer from nasal obstruction, sneezing, rhinorrhea and itchy nose. Additionally, nasal hyperreactivity (NHR) is present in more than 60% of patients with AR. NHR is defined as the induction of nasal symptoms after exposure to non-specific triggers in the environment. Many patients with AR are not well controlled, with several unmet therapeutic needs.

The nasal mucosa the first line of defense against the exposure to airborne allergens (pollen, house dust mite) and microbial (endotoxins) and environmental triggers (pollutants). Epithelial cells are tightly connected via junctions, such as tight junctions (TJ), forming a physical barrier. Changes in TJs affect the permeability and facilitate access of triggers to the submucosa. Proteolytic enzymes deriving from inhaled allergens can degrade TJs and induce epithelial barrier disruption. The triggers may subsequently interact with immune cells and/or neurons leading to activation and the release of mediators. These mediators affect other cells residing in the local environment resulting in symptoms.

Fluticasone propionate (FP), a corticosteroid used as mono-therapy for treatment of AR, may, in addition to its anti-inflammatory role, also increase the epithelial barrier integrity. Azelastine hydrochloride (AZE), a histamine (H)-1 receptor antagonist, reduces mast cell degranulation. The efficacy of the combination product of AZE and FP nasal spray was found to be superior compared to mono-therapy with better reduction of symptoms in patients with AR. However, the effect of this treatment on nasal mediators and/or NHR in patients with AR is still to be investigated. The impact of AZE in the presence or absence of FP on mast cells and neurons would help to understand the additional benefit of the combination product.

We hypothesize that a defective nasal barrier function induced by allergens, microbial and/or other environmental agents leads to increased access of environmental triggers and facilitate activation of mast cells and/or neurons. Additionally, AZE/FP nasal spray reduces NHR in patients with house dust mite AR partly be due to the restoration of the barrier integrity leading to reduced access of allergens to the submucosa, and thus, a decrease in mast cell and neuron activation. Finally, disruption of the nasal epithelial barrier may be the initial event required for allergic sensitization during the development of AR. The objective of this study is to investigate the impact of an epithelial barrier dysfunction on mast cell and/or neuronal activation in the nasal mucosa and on allergic sensitization.

Date:1 Nov 2013 →  7 Feb 2018
Keywords:Allergic rhinitis
Disciplines:Immunology
Project type:PhD project