The specific objectives of the proposed studies are to investigate the characteristics and regulation of the specialized transport mechanisms which exist in the pulmonary alveolar epithelium. We will further characterize the regulation of active sodium reabsorption from the airspaces to the blood across the adult mammalian alveolar epithelium of isolated perfused rat lungs. The ability to regulate the sodium transport processes will be elucidated by instilling radioisotopic tracers (22Na and 14C- sucrose) into the trachea and measuring the appearance of tracers in the recirculating perfusate. These measurements will be made during an appropriate control period as well as under the influence of a pharmacological agent or hormone known to affect transport rates (i.e., sodium transport inhibitors, beta-adrenergic agonists, cyclic AMP analogs, phosphodiesterase inhibitors, hydrocortisone, etc.). Changes in the apparent permeabilities of the isotopes from control values after the addition of the pharmacological agents will enable us to analyze the ability to regulate these transport mechanisms. In addition to investigating the regulation of active sodium fluxes across the blood-gas barrier, we will look at the regulation of glucose transport across the alveolar epithelium. In these experiments, changes in transport of 22Na and radioisotopically-labelled saccharides will be measured during control conditions as well as under the influence of various transport-regulating pharmacological agents (sodium transport blockers, beta-adrenergic agonists, glucose transport blockers, etc.). The regulation of the specialized sodium and glucose transport processes present in mammalian alveolar epithelium will first be investigated in isolated perfused rat lungs. Similar transport studies across isolated, perfused rabbit and hamster lungs will be conducted to determine the species variation of pulmonary alveolar epithelial transport mechanisms. It is our premise that the proposed studies of the alveolar epithelial barrier will lend insight into the mechanisms, regulation, and pathophysiology of formation and reabsorption of alveolar pulmonary edema under a number of different abnormal states of the lung, and may contribute to the development of improved preventive and therapeutic measures for the treatment of disorders involving this life-threatening condition in humans.
