The Initiation of Airway Eosinophilia and the Consequences of this Process on Acute and Chronic Bronchial Inflammation in Asthma are Unique and Complex. Included in this Process are the generation of airway cell cytokines, the interaction of eosinophil (EOS) surface receptors with key molecules in the lung microenvironment, and the molecular control of EOS-derived cytokines. The overall goal of this SCOR application is to establish mechanisms by which eosinophilic inflammation contributes to the pathogenesis of asthma at a pulmonary, cellular and molecular level. This SCOR proposal consists of five individual projects and two support CORE units, and will address three major areas of interest: (1) what is the cell source of cytokines (particularly IL-t) that regulate EOS recruitment to the airway? (2) What are the cellular consequences of EOS interactions with integrins and cytokines? And (3) What are the molecular mechanisms that regulate EOS cytokine (GM-CSF) production. In Project I, the SCOR clinical project, bronchoscopy with segmental antigen challenge will be performed to establish the phenotype(s) of the airspace cell(s) that generate(s) IL-5 in asthma and the abnormalities in the regulation of this process in asthma that lead to enhanced airway eosinophil migration and activation. To establish the uniqueness of IL- 5 effects in asthma, human subjects with allergic asthma (asthma), allergic rhinitis (atopy) and normals will be studies; this will provide us with the opportunity to distinguish the effects related to asthma vs. Atopy. Project II will investigate the molecular mechanisms associated with pulmonary eosinophilia in parainfluenza infected Brown Norway rats and the consequence of this on pulmonary physiology. The establishment of the molecular regulation of airway eosinophilia and altered lung function will be compared to the complement findings in Project I. In Project III, the consequences of selective matrix (fibronectin and laminin) integrin- EOS interactions on the EOS function will elucidated. Project IV will analyze the signal transduction processes in human EOS following IL-5 activation, and the relationship of these processes to EOS function. In Project V, human EOS will be transfected with the GM- CSF gene and the proposed studies will establish the molecular regulatory mechanisms for this cytokine in EOS. Core A will be responsible for bronchoscopy, biostatistics, and for providing airway cells and bronchial biopsy material for the individual projects. Core B, the eosinophil biology core, will provide isolated EOS for the various projects and will performance the various functional assays. It is proposed that this integrated, yet focused investigative, approach into mechanisms of eosinophilic inflammation in asthma will provide new and novel information relevant to asthma pathogenesis and the development of new treatment modalities.
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