A functional surfactant is critically required for normal respiration. The thin blood-gas barrier that includes the alveolar surfactant film must also be maintained free of chronic inflammation, a challenge in the face of daily exposure to thousands of liters of potentially contaminated air. The surfactant proteins, initially characterized on the basis of lipid-binding and biophysical activity, appear to contribute to both surfactant homeostasis and lung stability and a multilayered alveolar immune defense. Our broad objective is to provide a more mechanistic understanding of how the surfactant proteins perform these dual roles and their relative physiological significance. Our studies may ultimately be relevant to diseases directly linked to abnormal surfactant homeostasis such as acute respiratory distress syndromes (too little) and alveolar proteinosis (too much) as well as chronic inflammatory diseases such as BPD and COPD. We propose to test the general hypothesis that specific ligand recognition by discrete sequences and conformations of surfactant proteins A and D mediates dual and sometimes overlapping functions in surfactant physiology and host defense. Our study design is based on the truism that structure begets function. We will first characterize the structural basis of specific protein-ligand interactions and then explore the role of these interactions in alveolar physiology using a sequence of functional experiments. We will start with site-specific protein mutagenesis and in vitro biochemical and cellular assays and progress to studies in vivo using transgenic mouse models.