Activity of pulmonary surfactant protein-D (SP-D) in vivo is dependent on oligomeric structure

Pulmonary surfactant protein-D (SP-D) is a member of the collectin family o f C-type lectins that is synthesized in many tissues including respiratory epithelial cells in the lung. SP-D is assembled predominantly as dodecamers consisting of four homotrimeric subunits each. Association of these subuni ts is stabilized by interchain disulfide bonds involving two conserved amin o-terminal cysteine residues (Cys-IB and Cys-20), Mutant recombinant rat SP -D lacking these residues (RrSP-Dser15/20) is secreted in cell culture as t rimeric subunits rather than as dodecamers. In this study, transgenic mice that express this mutant were generated to elucidate the functional importa nce of SP-D oligomerization in vivo. Expression of RrSP-Dser15/20 failed to correct the pulmonary phospholipid accumulation and emphysema characterist ic of SP-D null (mSP-D-/-) mice. Expression of high concentrations of the m utant protein in wild-type mice reduced the abundance of disulfide cross-li nked oligomers of endogenous SP-D in the bronchoalveolar lavage fluid and d emonstrated a phenotype that partially overlapped with that of the SP-D-/- mice; the animals developed emphysema and foamy macrophages without the ass ociated abnormalities in alveolar phospholipids typical of SP-D-/- mice. De velopment of foamy macrophages in SP-D-deficient mice is not secondary to t he increased abundance of surfactant phospholipids. Disulfide cross-linked SP-D oligomers are required for the regulation of surfactant phospholipid h omeostasis and the prevention of emphysema and foamy macrophages in vivo.