The lungs are kept from collapsing by a material called surfactant, which is produced and secreted into the airspaces of the lung by one of the cell types which line the airspaces, type II alveolar epithelial cells. Abnormal production, secretion or reuptake of surfactant by type II cells results in diseases such as pulmonary alveolar proteinosis and infant respiratory distress syndrome. Little is known about how type II cells translate external modulatory signals (such as beta agonists) into changes in surfactant metabolism. Ion channels provide one important mechanism whereby many secretory and excitable cells modulate their function; we propose to determine the role of ion channels in type II cells in the production and secretion of surfactant. Technical advances in the past decade now make this proposal possible; first, type II cells may be isolated and studied in vitro. Second, the patch clamp technique has enabled electrical recording from cells as small as type II cells. We have studied isolated type II cells and found two types of voltage-gated potassium channels.
Our specific aims are (1) to correlate single channel currents with macroscopic currents (in order to characterize and compare currents to those in other cells and to estimate the impact of specific channel types on whole cell currents) (2) to search for chloride and calcium channels in type II cells, (3) to investigate the possibility that type II cells may be altered in vitro by isolation or identification procedures and (4) to correlate ion channel expression with surfactant synthesis and secretion. The last (and ultimately most important) aim may be accomplished by (a) comparing ion channels in cells actively secreting surfactant with those in cells that are not (b) testing drugs and physiological modulators of surfactant production and secretion for possible effects on ion channels. (c) testing specific ion channel blocking agents to see whether blocking a given ion channel inhibits surfactant production or secretion. The knowledge gained from this project may eventually enable rational pharmacological intervention in disease conditions exhibiting abnormal surfactant turnover. This project is well suited to by long term career goals of investigating physiologic and pathophysiologic regulatory mechanisms of cells in the respiratory system. The opportunity to advance both my career and knowledge about these mechanisms is made possible by close collaboration of the Departments of Medicine and Physiology in this institution.
