Asthma is a complex syndrome characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Although the development of airway inflammation and progression to persistent disease is multifactorial, it is the overall hypothesis of this SCOR that eosinophils (EOS) are pivotal cells in the pathogenesis of asthma. This assumption is based upon the EOS's cell and molecular biology, findings in human asthma, and animal models of inflammation. Preliminary results following treatment of asthmatic subjects with a monoclonal antibody against IL-5, however, have raised questions about the contribution of EOS to asthma. Consequently, this SCOR is designed to comprehensively address the role of EOS in asthma pathogenesis using a variety of in vivo and in vitro experiments involving human subjects, isolated EOS, and an animal model of asthma. Eosinophilic inflammation in asthma will be investigated at three levels: (1) the lung (Projects I and 11), (2) the isolated cell (Projects III and IV), and (3) the gene (Project V). This SCOR will evaluate the hypothesis that EOS participation in asthma requires (1) a first (priming) and second (activation) """"""""hit"""""""", (2) an IL-5-dependent and IL-5-independent phase of eosinophilic inflammation, and (3) the importance both of eosinophil activated phenotype and the vulnerable (asthmatic) airway to the generation of airway physiologic dysfunction. Project I will determine the effect of an asthma exacerbation on peripheral blood and, airway EOS priming, degranulation, transition from an IL-5-dependent to an IL-5-independent inflammatory process, and function as an antigen presenting cell. Project II proposes to """"""""add-back"""""""" EOS to a Brown Norway """"""""asthmatic"""""""" rat to determine the vulnerability of its airways to eosinophilic inflammation. The cellular consequences of EOS interactions with integrins, alpha4beta1, alpha4beta7 and alphaDbeta2, with VCAM-1 and fibronectin will be determined in Project III. Project IV will evaluate the effect of IL-5 on EOS signal transduction pathways in relationship to cell function and gene expression. Project V will evaluate the effect of YB-1, a nucleic binding protein, on GM-CSF mRNA stability. The three CORES will conduct bronchoscopy to obtain airway EOS (A), evaluate EOS function (B), and use new imaging techniques of the lung to characterize airway structure (C). This collaborative approach will provide a more precise understanding of the mechanisms of eosinophilic inflammation in relationship to the pathogenesis of asthma.
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