Inherited Surfactant Protein-B Deficiency and Surfactant Protein-C Associated Disease: Clinical Features and Evaluation

Edward Mallinckrodt Department of Pediatrics, Washington University and St. Louis Children's Hospital, St. Louis, MO 63110, USA.
Seminars in Perinatology (Impact Factor: 2.68). 01/2007; 30(6):316-26. DOI: 10.1053/j.semperi.2005.11.002
Source: PubMed


The pulmonary surfactant is a mixture of phospholipids and proteins synthesized, packaged, and secreted by alveolar type II cells that lowers surface tension and prevents atelectasis at end-expiration. A tightly regulated, complex metabolic cycle involves all components of the pulmonary surfactant. Disorders of surfactant metabolism that have a genetic basis are rare, but causes of respiratory dysfunction in infants and children emerge. Recessive loss of function mutations in surfactant protein-B (SP-B) gene lead to respiratory failure that is lethal in the newborn period while single allelic mutations in the surfactant protein-C (SP-C) gene cause interstitial lung disease of varying severity and age of onset. The genetic basis, mechanisms, clinical presentation and outcome, diagnostic approach and limited therapeutic options for disease due to mutations the SP-B and SP-C genes will be described in detail in this article. These disorders provide insights into some of the distinct mechanisms that disrupt the surfactant metabolic cycle and cause respiratory disease in infants and children.

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    • "They furthermore regulate the permeability of surfactant phospholipid membranes [20]. Inherited defects of SP-B and SP-C lead to respiratory failure and interstitial lung disease in early childhood [42]. Considering their ability to decrease surface tension, modulate the permeability of biomembranes and lower the viscosity of phospholipid layers [43], we assume that SP-B and SP-C are essential for the continuous secretion of CSF, the maintenance of its rheological properties and correct drainage into the arachnoid villi of the cerebral venous sinuses. "
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    ABSTRACT: Surfactant proteins (SP) have been studied intensively in the respiratory system. Surfactant protein A and surfactant protein D are proteins belonging to the family of collectins each playing a major role in the innate immune system. The ability of surfactant protein A and surfactant protein D to bind various pathogens and facilitate their elimination has been described in a vast number of studies. Surfactant proteins are very important in modulating the host's inflammatory response and participate in the clearance of apoptotic cells. Surfactant protein B and surfactant protein C are proteins responsible for lowering the surface tension in the lungs. The aim of this study was an investigation of expression of surfactant proteins in the central nervous system to assess their specific distribution patterns. The second aim was to quantify surfactant proteins in cerebrospinal fluid of healthy subjects compared to patients suffering from different neuropathologies. The expression of mRNA for the surfactant proteins was analyzed with RT-PCR done with samples from different parts of the human brain. The production of the surfactant proteins in the brain was verified using immunohistochemistry and Western blot. The concentrations of the surfactant proteins in cerebrospinal fluid from healthy subjects and patients suffering from neuropathologic conditions were quantified using ELISA. Our results revealed that surfactant proteins are present in the central nervous system and that the concentrations of one or more surfactant proteins in healthy subjects differed significantly from those of patients affected by central autoimmune processes, CNS infections or cerebral infarction. Based on the localization of the surfactant proteins in the brain, their different levels in normal versus pathologic samples of cerebrospinal fluid and their well-known functions in the lungs, it appears that the surfactant proteins may play roles in host defense of the brain, facilitation of cerebrospinal fluid secretion and maintenance of the latter's rheological properties.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "The lung biopsy in case 1 (NKX2-1-p.R165W) showed metaplastic alveolar type 2 epithelial cells, thickening of the alveolar septa, and accumulation of material in the alveolar lumen. Although this histopathologic pattern is not specific of SP-C or SP-B deficiency and may have been related in part to the prolonged use of mechanical ventilation, it is consistent with the classic patterns of lung disease associated with surfactant protein mutations [Hamvas, 2006]. In vivo, western blot analysis in case 2 (NKX2-1-p.L263fs) showed decreased levels of mature SP-C and SP-B proteins, and immunostaining of SP-B and SP-C was comparable in case 1 (NKX2-1-p.R165W) and in the control. "
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    ABSTRACT: NKX2-1 (NK2 homeobox 1) is a critical regulator of transcription for the surfactant protein (SP)-B and -C genes (SFTPB and SFTPC, respectively). We identified and functionally characterized two new de novo NKX2-1 mutations c.493C>T (p.R165W) and c.786_787del2 (p.L263fs) in infants with closely similar severe interstitial lung disease (ILD), hypotonia, and congenital hypothyroidism. Functional analyses using A549 and HeLa cells revealed that NKX2-1-p.L263fs induced neither SFTPB nor SFTPC promoter activation and had a dominant negative effect on wild-type (WT) NKX2-1. In contrast,NKX2-1-p.R165W activated SFTPC, to a significantly greater extent than did WTNKX2-1, while SFTPB activation was only significantly reduced in HeLa cells. In accordance with our in vitro data, we found decreased amounts of SP-B and SP-C by western blot in bronchoalveolar lavage fluid (patient with p.L263fs) and features of altered surfactant protein metabolism on lung histology (patient with NKX2-1-p.R165W). In conclusion, ILD in patients with NKX2-1 mutations was associated with altered surfactant protein metabolism, and both gain and loss of function of the mutated NKX2-1 genes on surfactant protein promoters were associated with ILD in "Brain-Lung-Thyroid syndrome".
    Full-text · Article · Feb 2010 · Human Mutation
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    ABSTRACT: Interstitial lung diseases (ILDs) in children constitute a heterogeneous group of rare diseases that have been described and classified according to experiences and research in adults. However, pediatric pulmonologists have observed that the clinical spectrum is broader in children than in adults, and that many of these disorders have different courses and treatment responses. In addition, probably due to the various stages of lung development and maturation, new clinical forms have been described, particularly in infants. This has broadened the classification of ILDs in this age bracket. The understanding that neither the usual definition nor the standard classification of these disorders entirely apply to children has prompted multicenter studies designed to increase knowledge of these disorders, as well as to standardize diagnostic and therapeutic strategies. We have reviewed the conceptualization of ILDs in children, taking into consideration the particularities of this group of patients when using the criteria for the classification of these diseases in adults. We have also made a historical review of several multicenter studies in order to further understanding of the problem. We have emphasized the differences in the clinical presentation, in an attempt to highlight knowledge of newly described entities in young children. We underscore the need to standardize management of laboratory and radiological routines, as well as of lung biopsy processing, taking such knowledge into account. It is important to bear in mind that, among the recently described disorders, genetic surfactant dysfunction, which is often classified as an idiopathic disease in adults, should be included in the differential diagnosis of ILDs.
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