The objective of the proposed research is to understand the mechanisms involved in the remodeling of lung structure typical of pulmonary conditions such as pulmonary emphysema and pulmonary fibrosis. The program is based upon two hypotheses: (1) a normal connective tissue framework is essential for normal lung structure and function so that restoration of normal lung structure after lung injury demands regaining a normal connective tissue framework, and (2) injury to the connective tissue framework of the lungs occurs principally through the action of degradative enzymes released from inflammatory cells in the lungs, many of which have been recruited to the lungs by chemotactic signals. The studies will focus upon fibronectin, collagen, elastin, and inflammatory cell-derived proteinases using protein biochemistry, immunologic procedures with both polyclonal and monoclonal antibodies, recombinant DNA, cell and tissue culture, ultrastructural analysis, and animal models of lung injury. The experiments will elucidate the role of fibronectin in maintaining normal cell-extracellular matrix relationships in the lungs and the effects of inflammatory cells upon fibronectin mediated events in the lungs. The modulation of connective tissue growth following lung injury will be examined by studying lung cell-derived factors that influence the proliferation of fibroblasts and their production of collagen. Ultrastructural methods will be used to evaluate the effects of selectively perturbing components of the extracellular matrix of the lungs. The degradative potential of human mononuclear phagocytes will be explored with cells at different stages of development in contact with native substrates and membranes resembling those of the lungs. Studies of elastin, a crucial component of the extracellular matrix of the lungs, are described involving elastin mRNA and the elastin gene, and the regulation of elastin synthesis from the standpoint of cell surface receptors on elastin producing cells which are responsive to factors in the extracellular matrix.
Showing the most recent 10 out of 333 publications
