Tissue remodeling of the extracellular matrix (ECM) is a dynamic process associated with physiologic and pathologic responses. We hypothesize that T cell- and/or APC-derived cytokines play a key role in the pathogenesis of tissue remodeling and tissue fibrosis. We will test this hypothesis in vitro: 1. Using cultured normal skin, keloid, and normal lung fibroblasts to define the differential pharmacologic activity and kinetics of specific cytokines (including Th2, Th1, Th0, and APC-derived cytokines) on total collagen, type-specific collagen, MMP, and TIMP generation. 2. Using a co-culture model of normal skin, keloid, or lung fibroblasts with antigen-stimulated Th0, Th1, or Th2 clones (previously characterized in our laboratory) or monocytes to refine the contributions of phenotype-specific T cell cytokines and APC-derive cytokines on total collagen, type-specific collagen, MMP, and TIMP generation. 3. Using the co-culture model to define the differential roles of model therapeutics including corticosteroids, phosphodiesterase inhibitors [theophylline (nonselective), rolipram (PDE4), siguazodan (PDE3)], calcineurin antagonists (cyclosporine, tacrolimus), antiproliferatives (mycophenolate mofetil), protein tyrosine kinase inhibitors (Genistein), and NF-?B inhibitors (BAY 1101) on T cell-, APC-, and fibroblast-specific contributions to tissue remodeling and tissue fibrosis.
