Role of the Intra-Epithelial Mast Cell in Acute and Chronic Asthma

University Of California, San Francisco, San Francisco CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): My long term goal is to better understand the biological mechanisms for acute asthma attacks, or "exacerbations." These acute attacks of asthma are responsible for most of the morbidity and mortality from asthma. Most exacerbations are caused by common respiratory viruses such as rhinoviruses. A particular inflammatory cell, the mast cell, is present in the airway lining and can respond to viral antigens by producing an array of inflammatory mediators that can produce asthma symptoms. Our hypothesis is that the intra-epithelial mast cell becomes activated in response to viruses and contributes to the pathogenesis of acute exacerbations. We also hypothesize that IL-13 production by the intra-epithelial mast cell promotes airflow obstruction and structural changes in the airway that affect lung function in chronic asthma. Specific Aim 1: To determine whether epithelial mast cells are activated during acute asthma exacerbations triggered by respiratory viruses. We will measure markers of mast cell activation in sputum and blood from 20 subjects presenting to the emergency room with acute exacerbations of asthma and 20 control subjects with acute exacerbations of COPD. Specific Aim 2: To determine whether mast cell numbers in the epithelial layer ("intra-epithelial mast cells") are increased in asthma, are related to airway dysfunction and pathology in asthma, and are a cellular source of IL-13 in the epithelium in asthma. We will quantify intra-epithelial mast cell number in bronchial biopsy tissues from 42 asthmatics and 28 healthy controls using rigorous stereological techniques. We will correlate mast cell number with measurements of airflow obstruction and chronic airway remodeling. Finally, we will identify the cellular source of IL-13 by co-localization immunohistochemistry. This research has significant implications for public health. The majority of asthmatics are well controlled with inhaled corticosteroids (ICS), but a subset of difficult asthmatics is prone to recurrent exacerbations and disproportionate use of healthcare resources. This results in 2 million requests for urgent care and 400,000 hospitalizations in the United States each year. Our research will hopefully lead to a better understanding of the mechanisms of exacerbations which should enable more effective methods for prevention and treatment of this common and serious public health problem. [unreadable] [unreadable] [unreadable]