Date of Award

2012

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Professor Richard W Costello

Second Supervisor

Professor Michael A Walsh

Keywords

Rhinitis, Allergic, Perennial, Nasal Mucosa

Abstract

Allergie rhinitis affects a large proportion of the worldwide population, and its constituent symptoms include nasal blockage, rhinorrhoea and nasal pruritus. Tissue acidosis is a component of inflammation and ischaemia, and this occurs in inflammatory conditions, such as that found in the mucosa of patients with allergic rhinitis.

Acid sensing ion channels, ASICs, are a family of ligand-gated cation channels, activated by acid (pH 7.4 — 5.5), which belong to the amiloride-sensitive degenerin/epithelial Na+ channel (ENaC) superfamily. Stimulation of these receptors on nerves leads to a variety of sensations including pain and mechanoperception, while epithelial expression linked to airway secretion has been reported in cystic fibrosis cell lines. A description and function of these receptors in human upper airways has not been described.

Our aim was to determine if the acid-sensing ion channel receptors, specifically type 3 (ASIC-3), are present, upregulated, and functional, in the nasal mucosa of patients with allergic rhinitis, and if they play a role in the allergic rhinitis constituent symptom of rhinorrhoea.

Eosinophils are almost always found in the mucosa, the submucosa and in the nasal secretions of subjects with allergic rhinitis. We hypothesised that the eosinophil has a major role to play in inflammatory conditions such as allergic rhinitis, and may have a role in acting via ASIC receptors, inducing them, or mediating them to react.

Our findings, as shown through real time polymerase chain reaction quantification of ASIC receptors in nasal biopsies, demonstrated no mRNA for ASIC-1 or ASIC-2. ASIC-3 was seen in both healthy controls and allergic rhinitis, in whom it was significantly increased (p

Functional experiments with lactic acid (pH 7.0) demonstrated significantly increased nasal secretary responses on the ipsilateral but not contralateral side, which were blocked by amiloride (ImM).

Eosinophils and released major basic protein (MBP) were found in association with airway nerve cells, mucous glands and epithelial cells. Eosinophil granule proteins increased the expression of ASIC-3 and showed a significant upregulation of ASIC-3 in an ERK-kinase dependent manner.

Thus, functional ASIC-3 receptors are present in nasal mucosa, and their expression is upregulated in allergic rhinitis via released eosinophil granule proteins. This data indicate a link with tissue inflammation, which may lead to enhanced nasal secretion in allergic rhinitis.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

2.81 MB

Comments

Submitted for the degree of Doctor of Medicine (MD) to the Royal College of Surgeons, 2012.

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