Genetic disorders of surfactant homeostasis

doi:10.1016/j.prrv.2006.04.191

Paediatric Respiratory Reviews

Volume 7, Supplement 1, 2006, Pages S240-S242

https://doi.org/10.1016/j.prrv.2006.04.191 Get rights and content

Summary

Pulmonary surfactant reduces surface tension at the air-liquid interface in the alveolus, thereby maintaining lung volumes during the respiratory cycle. In premature newborn infants, the lack of surfactant causes atelectasis and respiratory failure, characteristic of respiratory of distress syndrome. Surfactant is comprised of lipids and associated proteins that are required for surfactant function. Surfactant proteins B and C and a lamellar body associated transport protein, ABCA3 play critical roles in surfactant synthesis and function. Mutations in the genes encoding these proteins cause lethal respiratory distress in newborn infants. This review discusses the clinical and pathological findings associated with these inherited disorders of alveolar homeostasis.

Section snippets

Hereditary SP-B deficiency caused by mutations in SFTPB

SP-B is a 79 amino acid amphipathic protein. SP-B is packaged with phospholipids in the lamellar bodies, and secreted into the alveolus, where it stabilizes lipid films to reduce surface tension. SP-B or its precursor, proSP-B, regulate many aspects of surfactant homeostasis, being required for the processing of proSP-C, the formation of lamellar bodies, production of tubular myelin, the formation of active surfactant films, and the recycling of surfactant lipids and proteins. Deletion of the

SFTPC mutations and acute and chronic lung disease

SP-C is a 34 amino acid, hydrophobic, alpha-helical protein that is selectively synthesized type II epithelial cells in the lung. Human SP-C is produced by proteolytic processing of the larger precursor protein of 191 amino acids during its routing to the lamellar bodies. SP-C is packaged with surfactant lipids before being secreted into the airspace. Like SP-B, SP-C interacts closely with the phospholipids in surfactant, enhancing their spreading and stability, and likely mediating recruitment

ABCA3 transport protein and respiratory failure

ABCA3 is a member of a large class of Walker domain containing transmembrane proteins of ABC transporters known to translocate a number of substances across cell membranes. Related proteins include CFTR and other transmembrane proteins that are associated with human genetic diseases, including Tangiers disease, Stargardt's retinopathy, and others. Recent studies support the important role of ABCA3 in surfactant packaging and homeostasis. ABCA3 staining is found in alveolar type II epithelial

Summary

In summary, mutations in the genes encoding SP-B, SP-C, and ABCA3 disrupt surfactant homeostasis within type II epithelial cells and cause respiratory distress in newborn infants. Together these genes represent a relatively rare cause of acute and chronic lung disease in newborn infants and children. Diagnosis of the inherited disorders of surfactant homeostasis should be suspected in full-term infants with acute or chronic respiratory disease that is refractory to conventional therapies. Both

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There are more references available in the full text version of this article.

Cited by (21)

Respiratory Distress in Neonates: Underlying Causes and Current Imaging Assessment
2017, Radiologic Clinics of North America
Citation Excerpt :
The surfactant dysfunction disorders are a rare group of genetic diseases that lead to abnormal production and/or function of surfactant in the lungs, and can cause respiratory distress in the newborn. Several mutations have been identified, including mutations in genes for surfactant protein B (Fig. 9), surfactant protein C, adenosine triphosphate (ATP)-binding cassette transporter protein, thyroid transcription factor-1, and granulocyte-macrophage colony-stimulating factor–Rα.68–72 Patients affected with surfactant dysfunction disorder are typically born at term with respiratory distress.
Chronic interstitial lung disease in children: Diagnostic approach and management
2016, Archives de Pediatrie
Les pneumopathies infiltrantes diffuses chroniques (PID) regroupent un ensemble hétérogène d’affections rares qui ont en commun une atteinte des alvéoles et des tissus péri-alvéolaires conduisant à une perturbation des échanges gazeux. La démarche diagnostique D comporte trois étapes essentielles : reconnaître une PID, apprécier son retentissement et en identifier la cause. Les symptômes au moment du diagnostic ne sont pas spécifiques mais diffèrent selon les tranches d’âge. Chez le nouveau-né, le début est souvent brutal (détresse respiratoire néonatale) alors que chez le nourrisson le début est plus progressif (cassure pondérale, dyspnée, signes de lutte). Chez le grand enfant, le début est insidieux et le diagnostic est souvent posé à un stade évolué de la maladie. La démarche diagnostique repose sur des méthodes non invasives (anamnèse, examen clinique, tomodensitométrie thoracique, explorations fonctionnelles respiratoires) et invasives (lavage broncho-alvéolaire, biopsie pulmonaire transbronchique ou chirurgicale). La prise en charge thérapeutique des PID est difficile du fait de la multiplicité des causes. Les traitements non spécifiques visent à limiter l’inflammation et la fibrose (corticoïdes et immunosuppresseurs essentiellement). Ils sont associés aux traitements symptomatiques (oxygénothérapie, support nutritionnel, traitement de l’hypertension artérielle pulmonaire, vaccination). La transplantation est discutée en cas d’insuffisance respiratoire sévère.
Chronic interstitial lung disease (ILD) in children is a heterogeneous group of rare lung disorders characterized by an inflammatory process of the alveolar wall and the pulmonary interstitium that induces gas exchange disorders. The diagnostic approach to an ILD involves three essential steps: recognizing the ILD, appreciating the impact, and identifying the cause. The spectrum of clinical findings depends to a large extent on age. In the newborn, the beginning is often abrupt (neonatal respiratory distress), whereas there is a more gradual onset in infants (failure to thrive, tachypnea, indrawing of the respiratory muscles). In older children, the onset is insidious and the diagnosis can only be made at an advanced stage of the disease. The diagnosis is based on noninvasive methods (clinical history, respiratory function tests, chest X-ray, and high-resolution CT scan) and invasive techniques (bronchoalveolar lavage, transbronchial biopsy, video-assisted thoracoscopic biopsy, and open lung biopsy). The treatment of interstitial lung disease in children depends on the nature of the underlying pathology. The most common therapeutic approach involves the use of corticosteroids and immunosuppressive agents for their anti-inflammatory and antifibrotic effects. Children with ILD also need support therapy (oxygen therapy, nutritional support, treatment of pulmonary arterial hypertension, vaccination). Lung transplantation is discussed in patients with severe respiratory failure.
Surfactant phospholipid metabolism
2013, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Citation Excerpt :
SP-C mutations are linked to interstitial lung disease [270–272]. Mutations in ABCA3 are associated with both phenotypes [2,273]. Thus, the importance of phospholipids to mammalian life is absolute and abnormalities in surfactant phospholipid metabolism contribute pathobiologically to a diverse array of respiratory illnesses.
Pulmonary surfactant is essential for life and is composed of a complex lipoprotein-like mixture that lines the inner surface of the lung to prevent alveolar collapse at the end of expiration. The molecular composition of surfactant depends on highly integrated and regulated processes involving its biosynthesis, remodeling, degradation, and intracellular trafficking. Despite its multicomponent composition, the study of surfactant phospholipid metabolism has focused on two predominant components, disaturated phosphatidylcholine that confers surface-tension lowering activities, and phosphatidylglycerol, recently implicated in innate immune defense. Future studies providing a better understanding of the molecular control and physiological relevance of minor surfactant lipid components are needed. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
What does imaging the chest tell us about bronchopulmonary dysplasia?
2010, Paediatric Respiratory Reviews
Citation Excerpt :
Rarely children born preterm may develop severe chronic lung disease due to a cause other than BPD. Genetic abnormalities in surfactant proteins B and C and in ABCA-3 can all present as severe neonatal lung disease, and in these cases CT scan may be essential in the diagnosis of these rare conditions.11 In addition to it's role in the clinical evaluation of potential complications of BPD, through research studies, chest CT has given us significant insights in to both underlying pathology and long term outcome of BPD.
Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Chest imaging is important in making the diagnosis of BPD, and in assessing for complications. More recently computerised tomography (CT) scanning has provided insights in to the pathophysiology of BPD. Studies in infants, young and school age children as well as young adults have consistently demonstrated abnormalities in the peripheral lung, possibly related either to small airway or alveolar disease. Advances in CT scanning may increase the clinical role for this modality, in addition newer techniques such as hyperpolarised gas magnetic resonance imaging are likely to provide further insights in to the nature of BPD and its effects on the developing lung.
Deletion of Scap in alveolar type II cells influences lung lipid homeostasis and identifies a compensatory role for pulmonary lipofibroblasts
2009, Journal of Biological Chemistry
Pulmonary function after birth is dependent upon surfactant lipids that reduce surface tension in the alveoli. The sterol-responsive element-binding proteins (SREBPs) are transcription factors regulating expression of genes controlling lipid homeostasis in many tissues. To identify the role of SREBPs in the lung, we conditionally deleted the SREBP cleavage-activating protein gene, Scap, in respiratory epithelial cells (Scap^Δ/Δ) in vivo. Prior to birth (E18.5), deletion of Scap decreased the expression of both SREBPs and a number of genes regulating fatty acid and cholesterol metabolism. Nevertheless, Scap^Δ/Δ mice survived postnatally, surfactant and lung tissue lipids being substantially normalized in adult Scap^Δ/Δ mice. Although phospholipid synthesis was decreased in type II cells from adult Scap^Δ/Δ mice, lipid storage, synthesis, and transfer by lung lipofibroblasts were increased. mRNA microarray data indicated that SCAP influenced two major gene networks, one regulating lipid metabolism and the other stress-related responses. Deletion of the SCAP/SREBP pathway in respiratory epithelial cells altered lung lipid homeostasis and induced compensatory lipid accumulation and synthesis in lung lipofibroblasts.
High-throughput evaluation of pulmonary surfactant adsorption and surface film formation
2008, Journal of Lipid Research
Citation Excerpt :
A qualitative and quantitative evaluation of the performance of pulmonary surfactant preparations has traditionally required setting up specialized equipment typical of surface chemistry laboratories. Determination of the abilities of surfactant samples to form surface films rapidly and efficiently with equilibrium surface tensions below 30 mN/m, and at the same time to be capable of reaching extremely low tensions under compression, is crucial to assessing structure-function correlations in normal and altered surfactants (1, 4, 20) and to optimizing clinical preparations with therapeutic potentials (14–16). Most of the techniques traditionally used to evaluate pulmonary surfactant are based on the direct use of different types of surface balances to monitor the changes in surface tension that surfactant promotes.
The assessment of new therapeutic strategies to cure surfactant-associated lung disorders would greatly benefit from assay systems allowing routine evaluations of surfactant functions. We present a method to measure surfactant adsorption kinetics into interfacial air-liquid interfaces based on fluorescence microplate readers. The principle of measurement is simple, robust, and reproducible: Wells of a microtiter plate contain an aqueous solution of a light-absorbing agent. Fluorescence is excited and collected from the top of the wells so that fluorescently labeled surfactant injected into the bulk can be detected only once adsorbed into the air-liquid interface. Mass transfer from the bulk to the interface is achieved by orbital shaking implemented in the plate reader instrument. The method has been tested and validated by using phospholipids or surfactants of different origins, by using albumin as surfactant inhibitor, and by comparison of results with Wilhelmy balance measurements. The method is suited for implementation in high-throughput screening routines for conditions affecting, or improving, surfactant film formation. In contrast to surface tension measurements, our method gives a direct readout of the amount of surfactant adsorbing into the interface, including the functionally important amount of material firmly associating with the interfacial film.

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Genetic disorders of surfactant homeostasis

Summary

Section snippets

Hereditary SP-B deficiency caused by mutations in SFTPB

SFTPC mutations and acute and chronic lung disease

ABCA3 transport protein and respiratory failure

Summary

Hydrophobic surfactant proteins in lung function and disease

N Engl J Med

Genetic disorders influencing lung formation and function at birth

Hum Mol Genet