Surfactant protein-D regulates surfactant phospholipid homeostasis in vivo.
Surfactant protein D (SP-D) is a 43-kDa member of the collectin family of collagenous lectin domain-containing proteins that is expressed in epithelial cells of the lung. The SP-D gene was targeted by homologous recombination in embryonic stem cells that were used to produce SP-D (+/-) and SP-D (-/-) mice. Both SP-D (-/-) and SP-D (+/-) mice survived normally in the perinatal and postnatal periods. Whereas no abnormalities were observed in SP-D (+/-) mice, alveolar and tissue phosphatidylcholine pool sizes were markedly increased in SP-D (-/-) mice. Increased numbers of large foamy alveolar macrophages and enlarged alveoli were also observed in SP-D (-/-) mice. Phospholipid composition was unaltered in SP-D (-/-) mice, but surfactant morphology was abnormal, consisting of dense phospholipid membranous arrays with decreased tubular myelin. The pulmonary lipoidosis in the SP-D (-/-) mice was not associated with accumulation of surfactant proteins B or C, or their mRNAs, distinguishing the disorder from alveolar proteinosis syndromes. Surfactant protein A mRNA was reduced and, SP-A protein appeared to be reduced in SP-D (-/-) compared with wild type mice. Targeting of the mouse SP-D gene caused accumulation of surfactant lipid and altered phospholipid structures, demonstrating a previously unsuspected role for SP-D in surfactant lipid homeostasis in vivo.
Division of Pulmonary Biology, Department of Pediatrics, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA.
T R
TR
Korfhagen
V
V
Sheftelyevich
M S
MS
Burhans
M D
MD
Bruno
G F
GF
Ross
S E
SE
Wert
M T
MT
Stahlman
A H
AH
Jobe
M
M
Ikegami
J A
JA
Whitsett
J H
JH
Fisher
D000818:Animals; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D006579:Heterozygote; D006706:Homeostasis; D006720:Homozygote; D008064:Lipidoses; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010713:Phosphatidylcholines / Q000378:metabolism*; D011510:Proteolipids / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000032:analysis
D006023:Glycoproteins; D010713:Phosphatidylcholines; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D012333:RNA, Messenger