The goals of the proposed research are to study the characteristics and regulation of active and passive water and solute transport across the normal and abnormal pulmonary alveolar epithelial barrier. We will study the transport properties of two preparations of isolated alveolar epithelium. These preparations will be used to determine transport pathways of solutes and water, measure alveolar epithelial transport properties under various physiological and pathological conditions, and determine the role of the integrity of lung epithelial barriers on the mechanisms of pathogenesis and resolution of alveolar pulmonary edema. The overall premise of these studies is that information about the characteristics and regulation of the transport of water and solutes across alveolar epithelium per se will lead to further insight not only into the basic functions of this tissue, but also into the importance of such transport properties in the generation and removal of alveolar fluid. The investigations will follow the two-pronged approach of utilizing harvested mammalian alveolar epithelial cells in primary culture and the hollow lungs of amphibians. Monolayers of mammalian Type II cells will be studied on both porous and nonporous surfaces, and amphibian lungs will be studied as sacs and flat sheets. Specific studies of the passive transport properties of these two preparations will include determination of passive non-electrolyte fluxes (including permeabilities and reflection coefficients), water fluxes due to hydrostatic and/or osmotic pressure gradients, pathways for transport across alveolar epithelium, and the effects on transport of physicochemical parameters such as temperature and pH. Active transport studies will include measurements of bioelectric properties (including spontaneous potential differences, tissue resistance and short circuit current), active ion fluxes, water movements due to active solute transport, and the effects of certain hormones and drugs (including, for example, theophylline and ADH). It is anticipated that our studies will provide information on the characteristics and regulation of active and passive solute and water transport of the alveolar epithelial barrier. These data should help us understand mammalian alveolar epithelial transport properties, in normal and abnormal lungs, and their roles in the prevention, formation, and resolution of alveolar pulmonary edema in vivo.
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