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This Article Full Text Full Text (PDF) All Versions of this Article: 291/2/L181    most recent 00015.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Zhang, L. Articles by Whitsett, J. A. Search for Related Content PubMed PubMed Citation Articles by Zhang, L. Articles by Whitsett, J. A.

Neither SP-A nor NH₂-terminal domains of SP-A can substitute for SP-D in regulation of alveolar homeostasis

¹Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, and ²Pulmonary/Critical Care Division, University of Cincinnati Medical Center, Cincinnati, Ohio; ³Department of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; ⁴Department of Medicine and Department of Cell Biology and Physiology, Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri; and ⁵Pulmonary and Critical Care, Brigham and Women’s Hospital, Boston, Massachusetts

Submitted 10 January 2006 ; accepted in final form 20 February 2006

Surfactant proteins (SP)-A and -D are members of the collectin family of host defense proteins that share four distinct structural domains: NH₂-terminal oligomerization, collagenous, neck, and carbohydrate recognition (CRD). 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 NH₂-terminal and collagenous domains of SP-A with neck domain and CRD of SP-D; and 3) rSftpd/a, consisting of NH₂-terminal and collagenous domains of SP-D with neck domain and CRD 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 NH₂-terminal and collagenous domains, which 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 air space enlargement similar to Sftpd^–/– mice, supporting the concept that the increased expression of each metalloproteinase seen in Sftpd^–/– lungs is not the major cause of emphysema.

Sftpd^–/– mice; emphysema; lipid homeostasis; inflammation

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