期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 291, 期 2, 页码 L181-L190出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00015.2006
关键词
Sftpd(-/-) mice; emphysema; lipid homeostasis; inflammation
资金
- NHLBI NIH HHS [HL-47328, HL-63329, HL-58795, HL-56387, HL-68861] Funding Source: Medline
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.
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