Genetic disorders of surfactant homeostasis.
Adaptation to air breathing at birth requires the precise orchestration of cellular processes to initiate fluid clearance, enhance pulmonary blood flow, and to synthesize and secrete pulmonary surfactant needed to reduce surface tension at the air-liquid interface in the alveoli. Genetic programs regulating the synthesis of the surfactant proteins and lipids required for the production and function of pulmonary surfactant are highly conserved across vertebrates, and include proteins that regulate the synthesis and packaging of pulmonary surfactant proteins and lipids. Surfactant proteins B and C (SP-B and -C) are small, uniquely hydrophobic proteins that play important roles in the stability and spreading of surfactant lipids in the alveolus. Deletion or mutations in SP-B and -C cause acute and chronic lung disease in neonates and infants. SP-B and -C are synthesized and packaged with surfactant phospholipids in lamellar bodies. Normal lamellar body formation requires SP-B and a member of the ATP-binding cassette (ABC) family of ATP-dependent membrane-associated transport proteins, ABCA3. Mutations in ABCA3 cause fatal respiratory disease in newborns and severe chronic lung disease in infancy. Expression of SP-B, -C, and ABCA3 are coregulated during late gestation by transcriptional programs influenced by thyroid transcription factor-1 and forkhead box a2, transcription factors that regulate both differentiation of the respiratory epithelium and transcription of genes required for perinatal adaptation to air breathing.
Whitsett
Jeffrey A
JA
Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA. jeff.whitsett@cchmc.org
Wert
Susan E
SE
Xu
Yan
Y
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D051542:Hepatocyte Nuclear Factor 3-beta; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D037701:Pulmonary Surfactant-Associated Protein B / Q000096:biosynthesis / Q000235:genetics*; D037721:Pulmonary Surfactant-Associated Protein C; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000502:physiology
C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; C496503:Foxa2 protein, mouse; C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D010455:Peptides; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; C489679:SFTPC protein, human; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta