The overall goal is to define the catabolic pathways of surfactant in vivo. Surfactant clearance rates differ in developing and adult animals, and rates of clearance and metabolic fate are important factors that need to be considered in the use of exogenously administered surfactants for the treatment of respiratory distress syndrome in preterm infants and for the potential treatment of patients with the adult respiratory distress syndrome. Experiments are designed to evaluate possible effects of exogenous surfactants on endogenous surfactant metabolic pathways. These experiments utilize a combination of intravascular and intratracheal labels to trace the metabolism of surfactant phosphatidylcholine. Techniques will be developed to isolate lysosomes and multivesicular bodies from lung homogenates and primary isolates of type II cells. The subcellular fractionation scheme is designed to recover organelles that are components of surfactant recycling and catabolic pathways. These pathways will be probed by tracking radiolabeled surfactant phosphatidylcholine and phosphatidylcholine analogues (lyso phosphatidylcholine and the ether linked analogue) through lung and type II cell subcellular fractions. The radiolabeled analogues are chosen to permit more specific identification of the pathways and their function. The same subcellular fractionation technique will be applied to lung homogenates and type II cells from animals treated with radiolabeled surfactant following pretreatment with agents known to interfere with lysosomal catabolic activity (amiodarone and/or chlorphenteramine). These experiments are designed to evaluate the contribution of lysosomes to catabolism. Other experiments will combine radiolabeled hydrophobic surfactant proteins with surfactant to measure the clearance of the surfactant proteins and their effects on surfactant metabolism. These experiments then will be extended to a lung injury model induced by N-nitroso-N-methylurethane to evaluate the effects of lung injury on the catabolism and clearance of treatment doses of surfactant. The experiments in aggregate will quantify surfactant catabolic pathways, and the effects of development and lung injury on those pathways. By selective use of tract or treatment doses of surfactant, the results will characterize both normal pathways and pathways that may be important following surfactant treatment.

R37HD011932

1977-09-30

1998-03-31