We propose to study host defense mechanisms centered about the pulmonary macrophages as these cells first appear and mature in the respiratory system during fetal and neonatal life. Results of the research should improve understanding primarily of the development of phagocytic and associated functions of pulmonary macrophages as these occur in vivo or under lifelike experimental conditions in organ cultures of fetal lungs. A newly identified resident macrophage population of fetal lungs will be characterized, including its cytological makeup, mitotic activity, and emergent defensive capacity, as judged by cytochemical assay for lysosomal enzymes, estimates of phagocytic capability, and expression on the macrophage surface of Fc receptors and other markers of functional maturation. Intracellular pattersn of particle transport and lysosomal production will be examined in fetal macrophages present at different gestational ages and compared to patterns of low-level and high-level activity observable in macrophages from adult lungs, in order to obtain further evidence of the capacity of fetal cells. Experiments will be performed to determine if and when the initial macrophage population is supplemented by macrophages emigrating from the blood stream, and particularly if this occurs just before birth. A detailed timetable will be constructed for the appearance in the lungs of other leukocyte types with which macrophages interact (T and B lumphocytes, T cell subsets, null cells, plasma cells, mast cells). Routine surveys of fetal lungs will be carried out using semi-thin plastic embedded sections and high resolution light microscopy, so as to keep the panorama of pulmonary development in view while selected details are pursued by electron microscopy or by enzyme and immunocyto-chemistry. Studies on intracellular pathways will make use of heavy metal markers for ingested particles and lysosomal hydrolases, which will be identified by quantitative dispersive x-ray analysis. With a normal pattern of macrophage development worked out in the lungs of several mammalian species, we then proposed to inquire whether it can be altered by exposure of cells (in vivo and in organ culture) to organic and inorganic particles, by altering the oxygen content of the environment (in organ cultures), or by other experimental interventions.
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