Airway inflammation is a central feature of chronic asthma. However, the mechanisms underlying the persistence of inflammation in asthma are poorly understood. In this SCOR, each project will examine the molecular mechanisms of recruitment or phenotypic differentiation of cells that, by virtue of their long life span in the airway wall, are likely to contribute to the persistence of airway inflammation in asthma. One project will examine the mechanisms by which naive CD-4+ T cells differentiate into pathogenic effector cells. Specifically, this project will identify the temporal and cellular requirements for IL-4 priming, the role of costimulatory signals delivered through the CD28-B7 and CD40-CD40L pathways, and the potential to tolerize T cells and abrogate pathologic airway responses to antigen through the use of altered ligands. A second project will utilize the same model, and blocking antibodies and/or knockout mice, to directly examine the contributions of members of the selectin family to the recruitment of leukocytes into the airways and to the subsequent physiologic derangements of airway function. Additional experiments will identify the signals and pathways by which selectins activate integrins, and will identify and characterize the extra lymphoid endothelial ligand for L-selectin. Antibodies directed at two distinct families of leukocyte integrins inhibit airway hyperresponsiveness, an effect that does not depend solely on inhibition of leukocyte recruitment. A third project will examine the mechanisms by which anti-integrin antibodies could directly and indirectly affect airway leukocytes. These studies should provide insight into how remodeled airways can provide pathogenic signals to leukocytes that perpetuate airway dysfunction in asthma. A fourth project will examine the effects of signals from the extracellular matrix on the production of chemokines and other cytokines from airway epithelial cells. These studies will utilize anti-integrin antibodies and recombinant matrix protein fragments to specifically trigger signals through each of the integrins expressed on airway epithelial cells. They will then utilize transgenic mice expressing mutant integrins or integrin ligands to examine the significance of these effects on two different models of airway inflammation and hyperresponsiveness. A fifth project will examine the expression of the two principal chymotrypsin-like mast cell proteases in normal and inflamed human airways, and will utilize the regulatory regions of the genes encoding each of these proteases to examine the DNA sequences and nuclear proteins responsible for regulation of protease expression. Finally, a sixth project will examine the integrated responses of all of the cells in the airway wall of human subjects to challenge with experimental or community acquired viral infection or inhaled allergen. By examining many of the endpoints utilized in each of the other five projects, this project will insure rapid application of an basic observations made to the direct study of human asthma.
Showing the most recent 10 out of 12 publications
