Normal surfactant pool sizes and inhibition-resistant surfactant from micethat overexpress surfactant protein A

Pulmonary surfactant protein-A (SPA) has been reported to regulate the upta ke and secretion of surfactant by alveolar type II cells, to stabilize larg e surfactant aggregates including tubular myelin, and to protect the surfac e activity of surfactant from protein inhibitors. In this study we investig ated the consequences of overexpression of SP-A on pulmonary homeostasis an d surfactant function in transgenic mice. The human SP-C promoter was used to direct synthesis of rat surfactant protein A (rSP-A) in alveolar type II cells and nonciliated bronchiolar cells of the distal respiratory epitheli um. Levels of SP-A measured through enzyme-linked immunosorbent assay were 7- to 8-fold higher in lung homogenates and alveolar lavage fluid of the rS P-A mice than in those of transgene-negative littermates. The swimming exer cise tolerance and lung compliance of mice bearing the transgene were uncha nged. Mean air space sizes seen in randomly selected Light-microscopic fiel ds were not significantly different in the transgene-positive and -negative mice by morphometric analysis, but 15% of transgenic animals had scattered foci containing dilated alveoli and alveolar ducts without evidence of inf lammation or fibrosis. Some alveolar macrophages contained bar-shaped osmop hilic inclusions that had a highly ordered ultrastructure. There were no di fferences between the transgene-positive and -negative mice in the tissue o r alveolar pool sizes of saturated phosphatidylcholine or in the large-aggr egate composition of alveolar surfactant. The surface activity of surfactan t isolated from the rSP-A mice was similar to that of the controls, but in the presence of protein inhibitors, the surface tension-reducing properties of the rSP-A surfactant were better preserved (P < 0.05). We conclude that overexpression of SP-A does not affect resting surfactant phospholipid lev els, but that it enhances the resistance of surfactant to protein inhibitio n.