Hyaline membrane disease is a major factor in the morbidity and mortality associated with premature birth. This disease is now understood to be related to lack of synthesis and secretion of surfactant from alveolar Type II cells. The proposed study is designed to test the hypothesis that surfactant release from pulmonary epithelial cells is mediated by P2-purinoceptor activation, phosphatidylinositol turnover, calcium mobilization, protein kinase C activation, and subsequent phosphorylation of specific cellular proteins regulating release of surfactant. Secondly, it is proposed that the maturation of this response system, required for the ability of the newborn to adapt to extrauterine life, occurs in the perinatal period. It is predicted that the maturation of this response system is hormonally mediated and that there exists the potential for therapeutic regulation of the P2-purinoceptor system. Systematic studies will be undertaken to demonstrate P2-purinoceptors, phosphatidylinositol polyphosphate turnover, calcium mobilization, prostaglandin production, protein kinase C activation, and protein kinase C dependent phosphorylation reactions to identify the possible cellular mechanisms involved in surfactant release responses to P2-purinoceptor activation. Identification and characterization of the above activities will be performed in adult rat Type II cells and correlated with the characteristics of surfactant release. After clarification of the above regulatory events in the adult cell, more difficult studies to determine the development and maturation of this system is fetal lung will be performed. These later experiments will utilize short-term tissue culture of fetal Type II cells in serum-free medium to determine possible humoral regulation of the maturation of the various components of the P2-purinoceptor response system. The overall objective of the study is to determine the possible cellular mechanisms involved in the maturation of sufactant release which may play a role in the pathogenesis of hyaline membrane disease and other respiratory problems of both the prematurely born infant and adults.
