The role of homodimers in surfactant protein B function in vivo

Surfactant protein B (SP-B) is detected in the airways as a sulfhydryl-depe ndent dimer (M-r similar to 16,000). To test the hypothesis that formation of homodimers is critical for SP-B function, the cysteine residue reported to be involved in SP-B dimerization was mutated to serine (Cys(248) --> Ser ) and the mutated protein was targeted to the distal respiratory epithelium of transgenic mice. Transgenic lines which demonstrated appropriate proces sing, sorting, and secretion of human SP-B monomer were crossed with SP-B /- mice to achieve expression of human monomer in the absence of endogenous SP B dimer (hSP-B-mon, mSP-B-/-). In two of three transgenic lines, hSP-B- mon, mSP-B-/- mice had normal lung structure, complete processing of SP-C p roprotein, well formed lamellar bodies, and normal longevity. Pulmonary fun ction studies revealed an altered hysteresis curve for hSP-B-mon, mSP-B-/- mice relative to wild type mice. Large aggregate surfactant fractions from hSP-B-mon, mSP-B-/- mice resulted in higher minimum surface tension in vitr o compared with surfactant from wild type mice. Surfactant lipids supplemen ted with 2% hSP-B monomer resulted in slower adsorption and higher surface tension than surfactant with 2% hSP-B dimer, Taken together, these data ind icate a role for SP-B dimer in surface tension reduction in the alveolus.