This multidisciplinary program will apply the techniques and concepts of cell and molecular biology to study normal lung structure, alterations in lung structure due to inflammation, and alveolar surface proteins. The underlying hypothesis of this program is that extracellular matrix has a fundamental role in lung function and that disturbances in lung extracellular matrix have a key role in the pathophysiology of emphysema, pulmonary fibrosis, chronic forms of pulmonary hypertension, and other conditions in which lung architecture is seriously altered from normal. Specific themes to be explored in this proposal will be: (1) interactions between inflammatory cells and lung extracellular matrix and between inflammatory cells and lung cells; (2) production and degradation of lung extracellular matrix; (3) expression and regulation of surfactant- associated proteins; and (4) mechanisms of pulmonary vascular remodeling in pulmonary hypertension. A number of molecules will receive particular emphasis, including fibronectin, integrins alpha4beta 1 and alpha5beta1, vascular cell adhesion molecule-1 (VCAM-1), surfactant-associated protein-D (SP-D), entactin, interstitial collagenase, 92 Kda gelatinase, matrilysin, TIMP-2, and elastin. Transcriptional control of the genes of several of these molecules will be analyzed in detail. Studies of expression of these molecules will be performed using cells in culture, developing lungs, lung organ cultures, lungs of transgenic mice, and lungs of experimental animals with alveolar injury induced by bleomycin, hyperoxia, and tobacco smoke, and with pulmonary vascular abnormalities produced with monocrotaline and alveolar hypoxia. Human lung tissue will be analysed in some studies. Recombinant proteins will be expressed and subtraction libraries will be developed. 'In situ' hybridization for the localization of messenger RNAs in cells and tissues will be used extensively throughout the program. A specialized resource center, designated the morphology Core, will provide assistance with 'in situ' hybridization and other morphologic procedures, and in the development and application of immunologic and molecular reagents.
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