Correction of pulmonary abnormalities in Sftpd-/- mice requires the collagenous domain of surfactant protein D.
Surfactant protein D (SP-D) is a member of the collectin family of innate defense proteins. Members of this family share four distinct structural domains: an N-terminal cross-linking domain, a collagenous domain, a neck region, and a carbohydrate recognition domain. In this study, the function of the collagenous domain was evaluated by expressing a SP-D collagen deletion mutant protein (rSftpdCDM) in wild type and SP-D null mice (Sftpd(-/-)). rSftpdCDM formed disulfide-linked trimers that further oligomerized into higher order structures. The mutant protein effectively bound carbohydrate and aggregated bacteria in vitro. Whereas rSftpdCDM did not disrupt pulmonary morphology or surfactant phospholipid levels in wild type mice, the mutant protein failed to rescue the emphysema or enlarged foamy macrophages that are characteristic of Sftpd(-/-) mice. Moreover, rSftpdCDM partitioned with small aggregate surfactant in a manner similar to SP-D, but rSftpdCDM did not correct the abnormal surfactant ultrastructure or phospholipid levels observed in Sftpd(-/-) mice. In contrast, rSftpdCDM completely corrected viral clearance and the abnormal inflammatory response that occurs following pulmonary influenza A challenge in Sftpd(-/-) mice. Our findings indicate that the collagen domain of SP-D is not required for assembly of disulfide-stabilized oligomers or the innate immune response to viral pathogens. The collagen domain of SP-D is required for the regulation of pulmonary macrophage activation, airspace remodeling, and surfactant lipid homeostasis.
Kingma
Paul S
PS
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Zhang
Liqian
L
Ikegami
Machiko
M
Hartshorn
Kevan
K
McCormack
Francis X
FX
Whitsett
Jeffrey A
JA
D000818:Animals; D003094:Collagen; D017353:Gene Deletion; D006706:Homeostasis; D050356:Lipid Metabolism; D008168:Lung / Q000002:abnormalities* / Q000378:metabolism; D008171:Lung Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics* / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants; D011994:Recombinant Proteins; D003094:Collagen