The epithelium of chronically inflamed airways is characterized by mucus hypersecretion and shows 2 relevant adaptations: (a) mucous cell metaplasia, whereby individual epithelial cells differentiate to express mucin and (b) epithelial remodeling whereby the entire epithelial tissue layer becomes convoluted, invading connective tissue to form mucous crypts and glands. To identify molecular mechanisms underlying these changes requires the use of biochemical markers. Mucin can be considered a marker for mucous metaplasia as mucous differentiation is dependent on mucin gene expression. Metalloproteinases can be considered markers for epithelial remodeling as morphogenetic processes requiring connective tissue degradation are dependent on these enzymes. Seeking stimuli potentially controlling mucin and metalloproteinase expression in the inflamed airway we tested the effect of lymphocyte-derived cytokines. Product of both mixed lymphocyte reactions and fluid from asthmatic airways stimulated expression of the two markers at the RNA level. Experiments described below indicate that the Th2 cell mediator IL-9 is a major mucin stimulus in asthmatic airway fluid and that the T cell surface marker OX-47 (EMMPRIN) strongly stimulates metalloproteinases 1 and 9. Based on these relationships, we hypothesize that activated T cells in inflamed airways control mucous metaplasia and epithelial remodeling via IL-9 and EMMPRIN. Specific aim 1 will use mutant mice to determine which lymphocyte populations are required for M. pulmonis-induced mucin (Muc 5ac) and metalloproteinase (MMP-9) gene activation. Specific aim 2, using chemical inhibitors, dominant negative mutants and chimeric IL-9 receptor constructs, will test the hypothesis that IL-9 stimulates MUC5 AC in human bronchial epithelial cells via intersecting JAK-STAT and MAPK signaling pathways. Specific aim 3, using biochemical inhibitors, dominant negative mutants and a novel mutagenesis approach, will test the hypothesis that EMMPRIN stimulates MMP-1 in human fibroblasts via a p38-dependent mechanisms and will identify key elements of EMMPRIN-MMP signaling.
NIH ExPorter
NIH ExPorter