It is well documented that the human neonate is more susceptible to certain pulmonary infections than adults. The precise nature of the responsible immunologic defects and their relative importance are not well understood. In this regard, two unique conditions exist at birth which will form the basis of this investigation. The first condition relates to the immunosuppression exhibited by the fetus and neonate which is probably responsible for the stability of the fetal-maternal relationship. The second condition is brought about by the excess surfactant present at birth in relationship to a limited population of alveolar macrophages (AM), resulting in an overloading of AM with surfactant. Accordingly, the major objective of this study is to determine functional and biochemical time-dependent changes that rabbit resident AM undergo during early postnatal development as compared to AM from adults (1-2,7,14 and 28 day-old and 5-6 month-old). We will 1) examine relevant biochemical properties of AM and their isolated plasma membranes and 2) correlate these data with their functional capabilities as determined by in vitro techniques. Biochemical properties to be evaluated include, a) membrane lipid composition, b) membrane fluidity, c) quantitation of surface immunoreceptors, and d) oxidative metabolism. Functional capabilities to be studied include, a) random migration, b) chemotaxis, c) phagocytosis, d) bactericidal capacity, e) susceptibility to herpes virus infection, and f) antigen presentation. In addition, the effect of mediators such as a) muramyl dipeptide (MDP), glucan, phorbol myristate acetate (PMA), chemotaxins (f-met-leu-phe, C5a), lung surfactants and other cell-derived cytokines (MIF/MAF, MSF) on AM function will be evaluated. Our composite hypothesis states that, 1) following endocytosis of excess surfactant at birth, the early postnatal AM become physiologically and metabolically compromised and, therefore, their functional development and maturation are impaired, and 2) that the generalized down-regulated immune status of the neonate affects the level and rate at which AM functionally develop. The integrated efforts of three experienced investigators (Myrvik, immunobiology; Ricardo, immunochemistry, biochemistry and Kucera, virology) together with three expert collaborating investigators (Waite-membrane lipid chemistry, Parce-ESR and membrane fluidity analysis, and Bass-flow cytometry) should assure success of this project.
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