The overall goal is to understand how the lung regulates surfactant pools in health and disease. The hypothesis is that alveolar surfactant is regulated by cytokines/growth factors/hormones and that studies of surfactant metabolism and function in transgenic mice with abnormalities in these systems will provide insights into surfactant homeostasis. Although there is considerable information about the overall kinetics of metabolism of the major surfactant components - saturated phosphatidylcholine (Sat PC) and the surfactant associated SP-A, SP-B and SP-C, the relative contributions of type II cells, Clara cells, and macrophages to alveolar metabolism is not known. The contributions of these cell types to the metabolism will be evaluated in normal mice. Transgenic mice with alveolar proteinosis (GM-CSF-I-,IL-4 overexpression) and pulmonary fibrosis (TGFalpha overexpression) will be used to identify the metabolic pathway(s) and/or cell types responsible for the abnormalities in surfactant homeostasis. Measurements will be made of precursor incorporation into Sat PC and the surfactant proteins, secretion and alveolar and lung clearances of these surfactant components. Surfactants of abnormal composition resulting from transgenic constructs that lack SP-A or SP-D, overexpress SP-A, and overexpress SP-A and SP-B will be evaluated for in vitro biophysical properties and function to learn the ranges of surfactant function consistent with relatively normal lung function. Because the abnormalities in surfactant in these transgenic mice are similar to those encountered in patients with alveolar proteinosis, pulmonary fibrosis, other lung injuries and bronchopulmonary dysplasia, the results will provide a framework to understand surfactant metabolic abnormalities in human lung diseases.

R01HD011932

1977-09-30

2003-03-31