The collagen-like region of surfactant protein A (SP-A) is required for correction of surfactant structural and functional defects in the SP-A null mouse

Pulmonary surfactant isolated from gene-targeted surfactant protein A null mice (SP-A(-/-)) is deficient in the surfactant aggregate tubular myelin an d has surface tension-lowering activity that is easily inhibited by serum p roteins in vitro. To further elucidate the role of SP-A and its collagen-li ke region in surfactant function, we used the human SP-C promoter to drive expression of rat SP-A (rSPA) or SP-A containing a deletion of the collagen -like domain (Delta G8-P80) in the Clara cells and alveolar type II cells o f SP-A(-/-) mice. The level of the SP-A in the alveolar wash of the SP-A(-/ -,rSP-A) and SP-A(-/-,Delta G8-P80) mice was 6.1-and 1.3-fold higher, respe ctively, than in the wild type controls. Tissue levels of saturated phospha tidylcholine were slightly reduced in the SP-A(-/-,rSP-A) mice compared wit h SP-A(-/-) littermates. Tubular myelin was present in the large surfactant aggregates isolated from the SP-A(-/-,rSP-A) lines but not in the SP-A(-/- ,Delta G8-P80) mice or SP-A(-/-) controls. The equilibrium and minimum surf ace tensions of surfactant from the SP-A(-/-,rSP-A) mice were similar to SP -A(-/-) controls, but both were markedly elevated in the SP-A(-/-,Delta G8- P80) mice. There was no defect in the surface tension-lowering activity of surfactant from SP-A(+/+,Delta G8-P80) mice, indicating that the inhibitory effect of Delta G8-P80 on surface activity can be overcome by wild type le vels of mouse SP-A. The surface activity of surfactant isolated from the SP -A(-/-rSP-A) but not the SP-A(-/-,Delta G8-P80) mice was more resistant tha n SP-A(-/-) littermate control animals to inhibition by serum proteins in v itro. Pressure volume relationships of lungs from the SP-A(-/-), SP-A(-/-rS P-A), and SP-A(-/-,Delta G8-P80) lines were very similar. These data indica te that expression of SP-A in the pulmonary epithelium of SP-A(-/-) animals restores tubular myelin formation and resistance of isolated surfactant to protein inhibition by a mechanism that is dependent on the collagen-like r egion.