Neither SP-A nor NH2-terminal domains of SP-A can substitute for SP-D in regulation of alveolar homeostasis.
Surfactant proteins (SP)-A and -D are members of the collectin family of host defense proteins that share four distinct structural domains: NH(2)-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) NH(2)-rSftpa/d, consisting of NH(2)-terminal and collagenous domains of SP-A with neck domain and CRD of SP-D; and 3) rSftpd/a, consisting of NH(2)-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 NH(2)-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. NH(2)-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 NH(2)-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.
Zhang
Liqian
L
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, OH 45229, USA.
Ikegami
Machiko
M
Korfhagen
Thomas R
TR
McCormack
Francis X
FX
Yoshida
Mitsuhiro
M
Senior
Robert M
RM
Shipley
J Michael
JM
Shapiro
Steven D
SD
Whitsett
Jeffrey A
JA
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D006706:Homeostasis; D008055:Lipids / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics / Q000378:metabolism*; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D008055:Lipids; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D011993:Recombinant Fusion Proteins