MECHANISMS OF CHEMOKINE EXPRESSION IN ASTHMA

Brigham And Women'S Hospital, Boston MA

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Abstract

Asthma associated morbidity, disability effects 54 out of every 1000 Americans. This chronic recurrent disease is known to be directly associated with inflammation of the airways. Asthmatic airways are infiltrated with inflammatory cells including eosinophils which are present even in asymptomatic asthmatics with normal lung function. Eosinophils in asthmatic airways are activated and release preformed toxic granular proteins; they contain peroxidases which generate toxic oxygen metabolites, they generate lipid mediators and proinflammatory cytokines which can produce airway hyperresponsiveness-the cardinal physiological feature of asthma. The importance of eosinophils to asthma is suggested by studies that correlate the resolution of asthma symptoms with the resolution of airway eosinophilia. Defining the mechanisms that selectively recruit eosinophils to the airways has the potential to identify novel therapeutic targets relevant to eosinophil mediated diseases including asthma. While many substances are chemotactic for eosinophils far fewer have chemotactic effects that are selective for cell types assoicated with asthma. Eotaxin is one substance that selectively activates these cell types. The discovery of eotaxin in an animal model of asthma has led to investigations of its associations with human disease. Indeed we have recently found that eotaxin is mobilized in asthmatic lungs after segmental allergen challenge and airway levels correlate with the numbers of eosinophils recruited into the lungs. Eotaxin is detectable in human plasma and is directly and independently associated with asthma diagnosis, and inversely related to baseline lung function. Eotaxin levels are increased in asthma exacerbations and elevated levels are associated with worse outcomes from acute asthma care. Our long term goal is to understand the mechanisms that mobilize eotaxin and related chemokines that recruit eosinophils to the airways. We propose to study the mechanisms that are responsible for eotaxin mobilization by studying its mobilization in in vitro systems, and in cells from subjects with common eotaxin polymorphisms that impair eotaxin expression. Specifically we propose: (1) To determine the mechanism(s) by which a coding region polymorphism of the eotaxin gene reduces eotaxin expression. (2) To define the mechanisms that alter eotaxin mRNA expression. (3) To explore mechanisms common to eotaxin and MCP-4 mobilization and define regulatory elements critical for the coordinated expression of these chemokines. This work will lead to a better understanding of the mechanisms by which eotaxin and the CCR3 receptor contribute to the asthamtic diathesis.