Abnormalities of lung mechanics and gas exchange with acute lung injuries result directly from alterations in the surfactant system. There is almost no information concerning normal surfactant homeostasis or surfactant homeostasis with lung injury other than the knowledge that the system is metabolically active and responsive to physiological stimuli. The projects will utilize transgenic mice with abnormalities in surfactant components and regulation and newly constructed knockout and bitransgenic mice to ask which factors influence which cell types to maintain surfactant homeostasis. The projects will focus on 1) the normal alveolar forms and catabolic pathways of surfactant components and the effects of altered surfactant protein content on surfactant function, 2) the structural requirements for the intracellular trafficking, secretion and function of SP-3 and 3) the importance of SP-A in non-immune and biologic measurements of surfactant component processing and trafficking in vitro, recycling and catabolism in vivo and studies of mechanisms of host defense response of the lung. The three projects will be closely integrated by common themes and by the use of similar transgenic mouse models. The goal is to develop a better assessment of surfactant function in health and the contributions of surfactant abnormalities to disease. An understanding of how surfactant is regulated will lead to new strategies for improving surfactant function in diseases such as ARDS, viral pneumonias and alveolar proteinosis.