Inhaled nitric oxide (NO) is a novel clinical therapy that may reduce morbidity and mortality in many neonatal pulmonary diseases. The long term objectives of this research are 1) to establish whether inhaled nitric oxide enhances or hinders the phagocytic killing of bacteria by alveolar macrophages and 2) to define the oxidant stresses placed on alveolar macrophages by inhaled nitric oxide. Our hypotheses propose that 1) low concentrations of inhaled NO in an ambient environment (normoxia) enhance maturation of bactericidal mechanisms of newborn pulmonary alveolar macrophages, thereby augmenting their ability to ingest and kill bacteria, and 2) high doses of inhaled NO, either alone or in combination with high inspired oxygen concentrations (hyperoxia), will damage the nascent bactericidal mechanisms of newborn pulmonary alveolar macrophages, thereby reducing their antibacterial activity. The first hypothesis is related to nitric oxide's role; as an immunoregulatory agent, while the second hypothesis is a result of nitric oxide's action as an oxidant.
Our Specific Aims i nvestigate these hypotheses in a newborn piglet model that inhales NO either acutely or chronically. After environmental exposures, newborn alveolar macrophages are recovered by lung lavage and tested to: 1. Determine whether inhaled NO alters the in vitro phagocytosis and killing of Streptococcus agalactiae and Escherichia coli by newborn alveolar macrophages 2. Examine whether inhaled NO quantitatively reduces the O2-dependent (respiratory burst) and O2-independent (lysosomal) bactericidal mechanisms of newborn alveolar macrophages 3. Measure whether inhaled NO reduces the pro-inflammatory secretory activity of newborn alveolar macrophages which, in turn, modulates their antibacterial responses in an autocrine manner 4. Ascertain the extent to which inhaled NO modifies the DNA, proteins, and lipids of newborn alveolar macrophages coincident with alterations in cell function The knowledge obtained from this research will provide basic information required for the safe clinical use of inhaled nitric oxide in pulmonary diseases of newborns, children, and adults.
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