The airway wall in asthma is characterized by both the presence of chronic inflammation and by alteration of tissue structure. The current proposal will explore the mechanisms by which inflammation can cause tissue remodeling and, in particular, will evaluate the concept that paracrine factors serve to integrate the action of diverse inflammatory cytokines. The proposal will evaluate; 1) fibroblast mediated contraction of extracellular matrix, a form of tissue remodeling thought to contribute to airway narrowing and airflow limitation and amenable to in vitro investigation; 2) fibroblast degradation of extracellular matrix; and 3) matrix regulation of fibroblast apoptosis. Cytokines present in the inflammatory milieu in asthma, specifically IL-4 and IL-13 will be evaluated, and the concept that these cytokines act through the release of secondary paracrine mediators, specifically PGE, fibronectin and NO will be tested. The role of these paracrine factors in integrating and coordinating the actions of IL-4 and IL-13 with other cytokines will be tested using TGF-beta and TNF alpha. Finally, the behavior of fibroblasts derived from both normal and asthmatic tissues will be compared. The proposed studies should, therefore, help to define the mechanisms by which inflammatory mediators can regulate remodeling processes in the airway in asthma.
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