The goals of the proposed research are to study the characteristics and regulation of active and passive water and solute transport across the pulmonary alveolar epithelial barrier, and to understand their roles in alveolar homeostasis and edemagenesis. We will study these transport properties using two preparations of isolated alveolar epithelium, in addition to the intact epithelium of the perfused rat lung. The overall premise of our program is that information about the characteristics and regulation of the transport of water and solutes across alveolar epithelium will lead to further insight not only into the basic functions of this tissue barrier, but also into the importance of such transport properties in the generation and removal of alveolar fluid under normal and abnormal conditions. The investigations will follow a multi-pronged approach of utilizing the two isolated epithelial preparations (mammalian alveolar epithelial cells in primary culture, and the hollow lungs of amphibians) to generate fundamental information about transport across the alveolar epithelial barrier. Mammalian type Ii cells will be studied primarily as monolayers n porous surfaces, and amphibian lungs will be studied as sacs and flat sheets. Information generated in these basic investigations will be compared to that from studies of transport across the intact alveolar epithelium of the perfused mammalian lung. Specific studies of the passive transport properties of these preparations will include determination of passive solute permeabilities, water flux due to hydrostatic and/or osmotic pressure gradients, and pathways for transport across the alveolar epithelium. Active transport studies will include measurements of bioelectric properties (including spontaneous potential difference, tissue resistance and short circuit current), active ion (sodium) fluxes, and water movements due to active solute transport. Investigation of the effects of physiocochemical parameters (e.g., temperature, pH), pharmacological agents (e.g., hormones), and especially lung injury (e.g., by oxidants) constitute a major part of this proposal. It is anticipated that our investigations will provide further insight into the transport characteristics of the alveolar epithelial barrier in normal and abnormal adult mammalian lungs, and into the roles of these barrier properties in normal alveolar homeostasis and alveolar pulmonary edema in vivo.
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