The overall goals of this SCOR proposal are to understand how inflammatory cells infiltrate the pulmonary airway in asthma and how the resulting infiltrate leads to characteristic pathologic changes in airway tissue. The SCOR consists of five Projects that address five critical (and sequential) steps in this process: thus, initial recruitment of inflammatory cells (especially T cells and eosinophils) from the circulation appears to depend on interleukin-4 (IL-4)-driven expression of a cell adhesion molecule (VCAM-1) on the endothelial cell surface. This possibility is supported by evidence of increased levels of immune-cell IL-4 and endothelial-cell VCAM-1 in tissue from asthmatic subjects as well as inhibition of antigen-induced airway inflammation in animals lacking the IL-4 gene or treated with anti-VCAM-l antibodies. Accordingly, Project I aims at determining the molecular controls for IL-4 generation, and Project II aims at the controls for subsequent IL-4-stimulation of VCAM-I expression. Once inflammatory cells are recruited from the circulation, they are often directed towards the epithelial surface. Accordingly, Project III aims at determining the controls for another cell adhesion molecule (ICAM-1) that may influence the movement of the inflammatory cells after they arrive in the airway tissue. This possibility is also supported by evidence of increased epithelial ICAM-1 expression in asthmatic tissue as well as inhibition of antigen-induced inflammation in animals with anti-ICAM-1 antibodies. We have found that ICAM-1 expression is regulated by a member of the STAT family of transcription factors (designated Stat1), so special emphasis is given to Stat1-dependent gene activation and the consequent comparison of Th1- vs Th2-type T cell responses. Finally, the infiltration and activation of inflammatory cells in the asthmatic airway leads to characteristic pathology (especially epithelial damage), and two of the factors that may contribute to this cytopathology are eosinophil-derived matrix metalloproteinase and epithelial cell- or immune cell- derived nitric oxide. Accordingly, Project IV focuses on controls for a specific matrix metalloproteinase (92-kDa gelatinase) that has the capacity to mediate epithelial cell detachment and is selectively upregulated in tissue eosinophils. Project V aims at determining the role of cytokine-dependent nitric oxide generation in mediating epithelial cytopathology in asthma. These five projects are supported by four cores: the Administrative Core will perform administrative functions and will provide computer support for electronic communication and data analysis. The Human Subjects Core will devise clinical protocols, recruit and characterize research subjects, and obtain biologic material for investigators. The immunopathology Core will provide facilities for tissue processing from human subjects and from transgenic and gene- disrupted mice. The Transgenic/Gene-Disruption Mouse Core will supply and house these mice. Core/Project interactions are based on the principle that projects begin with molecular hypothesis- building in isolated-cell and mouse models and then extends the findings in these models to studies of human subjects with asthma.
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