Surfactant proteins A and D are members of collectin family of host defense proteins that share four distinct structural domains: N-terminal oligomerization, collagenous, neck and carbohydrate recognition. To determine the specificity of the functions of these domains, the SFTPC promoter was used to express: 1) full-length rat (r) Sftpa; 2) NH₂-rSftpa/d, consisting of the N-terminal and collagenous domains of SP-A with the neck and CRD domains of SP-D; and 3) rSftpd/a, consisting of the N-terminal and collagenous domains of SP-D with the neck and CRD domains of SP-A in Sftpd^-/- mice. Increased expression of SP-A in Sftpd^-/- mice did not correct the increased pulmonary saturated phosphatidylcholine levels, emphysema or foamy alveolar macrophage and lymphocyte infiltrations characteristic of Sftpd^-/- mice, indicating that the decreased SP-A level noted in Sftpd^-/- mice does not account for the observed pulmonary abnormalities. The chimeric protein NH₂-rSftpa/d was expressed and detected in the airways of transgenic mice, migrating as an SP-A like oligomer that associated with large aggregate surfactant in a manner similar to that of SP-A rather than SP-D. NH₂-rSftpa/d did not correct emphysema, foamy macrophage and lymphocyte infiltration or the increased lipid accumulations characteristic of Sftpd^-/- mice. Thus oligomerization and surfactant lipid association of SP-D requires its N-terminal and collagenous domains that are needed for SP-D dependent regulation of surfactant homeostasis in vivo. Attempts to express rSftpd/a fusion protein in vivo were unsuccessful. Mmp9^-/-/Sftpd^-/- and Mmp12^-/-/Sftpd^-/- mice developed airspace enlargement similar to Sftpd^-/- mice, supporting the concept that the increased expression of each metalloproteinase seen in Sftpd^-/- lungs was not the major cause of emphysema.