SP-B deficiency causes respiratory failure in adult mice (original) (raw)
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A major deletion in the surfactant protein-B gene causing lethal respiratory distress
Acta Paediatrica, 2007
Background: Loss of function mutations in the surfactant protein-B gene (SFTPB) cause lethal neonatal respiratory distress due to reduced or absent expression of mature surfactant protein B (SP-B, encoded in exons 6 and 7). No large deletions in SFTPB have been previously identified.Aim: Genomic, proteomic and immunohistochemical characterization of a 3 kb deletion in SFTPB.Methods: A full-term newborn presented with refractory respiratory failure. We amplified and sequenced SFTPB from the infant and both parents, determined SP-B protein expression in tracheal aspirate samples using Western-blot analysis, and performed immunohistochemical staining and electron microscopy of lung biopsy tissue.Results: The infant was homozygous for a 2958 bp deletion in SFTPB that included exons 7 and 8. Both asymptomatic parents were heterozygous for the deletion. A truncated mature SP-B peptide was detected on Western blotting of tracheal aspirate. Amino acid sequence specific to that encoded in exon 5 was present, but that encoded by exon 7 was absent. ProSP-B expression was robust within alveolar type II cells and lamellar body structure was disrupted.Conclusions: This deletion in SFTPB resulted in SP-B deficiency due to absence of elements in mature SP-B that are critical for appropriate peptide folding, trafficking and processing.
Reversibility of lung inflammation caused by SP-B deficiency
AJP: Lung Cellular and Molecular Physiology, 2005
Whereas decreased concentrations of surfactant protein (SP)-B are associated with lung injury and respiratory distress, potential causal relationships between SP-B deficiency and lung inflammation remain unclear. A transgenic mouse in which human SP-B expression was placed under conditional control of doxycycline via the CCSP promoter was utilized to determine the role of SP-B in the initiation of pulmonary inflammation. Adult mice, made SP-B deficient by removal of doxycycline, developed severe respiratory failure within 4 days. Deficiency of SP-B was associated with increased minimal surface tension of the surfactant and perturbed lung mechanics. Four days of SP-B deficiency did not alter SP-C content or surfactant phospholipid content or composition. SP-B deficiency was associated with lung inflammation and increased soluble L-selectin, STAT-3, and phosphorylated STAT-3 in alveolar macrophages and alveolar epithelial cells. Alveolar IL-6, IL-1β, and macrophage inflammatory protei...
An alternatively spliced surfactant protein B mRNA in normal human lung: disease implication
Biochemical Journal, 1999
We identified an alternatively-spliced surfactant protein B (SP-B) mRNA from normal human lung with a 12 nt deletion at the beginning of exon 8. This deletion causes a loss of four amino acids in the SP-B precursor protein. Sequence comparison of the 3h splice sites reveals only one difference in the frequency of U\C in the 11 predominantly-pyrimidine nucleotide tract, 73 % for the normal and 45 % for the alternatively-spliced SP-B mRNA (77-99 % for the consensus sequence). Analysis of SP-B mRNA in lung indicates that the abundance of the alternativelyspliced form is very low and varies among individuals. Although the relative abundance of the deletion form of SP-B mRNA remains constant among normal lungs, it is found with relatively
Surfactant protein B and A concentrations are increased in neonatal pneumonia
Pediatric Research, 2015
Translational Investigation nature publishing group Background: Term newborns with pneumonia show a reduced pulmonary compliance due to multiple and illdefined factors. Surfactant proteins' (SPs) changes could have a role in the reduced compliance but the matter is still unsettled. The aim of this study was to clarify the meaning of SPs changes during pneumonia in term newborns. Methods: In 28 term ventilated newborns, 13 with pneumonia and 15 with no lung disease, we measured SP-B, SPA , disaturated-phosphatidylcholine (DSPC), and total phospholipids (PL) concentrations in tracheal aspirates at intubation and close to extubation. We also measured DSPC kinetics using (U-13 C-PA)dipalmitoyl-phosphatidylcholine. results: At baseline, SP-B, expressed as % of PL, was significantly different between the groups, being 3.5-fold higher in pneumonia than controls. Conversely, SPA did not vary between the groups. At extubation, SP-B and SPA concentrations had decreased significantly in newborns with pneumonia, while there was no significant change in controls. DSPC t 1/2 was significantly shorter in the pneumonia group (11.8 (5.5-19.8) h vs. 26.6 (19.3-63.6) h, P = 0.011). conclusion: In term newborns with pneumonia, SP-B increases with respect to PL, and DSPC is turned over at a faster rate. Disease's resolution is associated with the restoration of the normal ratio between SP-B and PL. a lveolar surfactant is essential for lung stability and its composition and functional state are altered during pneumonia and acute respiratory distress syndrome (1,2). Pulmonary surfactant also plays an important role on the innate immune system by enhancing pathogen clearance and by regulating immune-cell functions (3). Surfactant proteins (SPs) represent less than 10% of total surfactant weight but they play a pivotal role on its function. SP-B is a hydrophobic protein that is considered to be the most important protein for sustaining respiratory physiology (4). SP-B enhances lipid insertion into the monolayer at the air/liquid interface (5), it is involved in the formation of tubular myelin (6), and it may also be part of the host defense mechanisms (7). SPA , a pulmonary
Hum Mut, 1999
Several human respiratory disorders have been linked to an abnormality of pulmonary surfactant synthesis or turnover. Among those conditions, hereditary deficiency in the hydrophobic surfactant protein B (SP-B) has been recognized as a rare cause of respiratory failure in term newborn infants. Homozygosity for a common mutation (1549C®GAA, or 121ins2) of the SP-B-encoding gene (SFTPB) results in rapidly fatal respiratory failure, with complete absence of the mRNA and protein observed in lung fluid or biopsy specimens. Hereditary SP-B deficiency is also associated with aberrant processing of proSP-C and deficiency of the active SP-C peptide. In the present study, we characterized the SFTPB gene in an infant with severe unexplained respiratory distress and identified a paternally derived 1549C®GAA lesion, as well as a hitherto unreported mutation (457delC) inherited from the mother. Analysis of bronchoalveolar lavage fluid demonstrated the complete absence of SP-B. However, unlike previous infants with hereditary SP-B deficiency, proSP-C was processed to the active SP-C peptide, suggesting that the defect in SP-B, rather than SP-C, caused the respiratory distress in this infant. The present findings demonstrate the importance of SFTPB in pulmonary function and support the need for further genotype-phenotype correlations in patients with SP-B deficiency. Hum Mutat 14:502-509, 1999.
Progressive Lung Disease and Surfactant Dysfunction with a Deletion in Surfactant Protein C Gene
American Journal of Respiratory Cell and Molecular Biology, 2004
Mutations in the surfactant protein (SP)-C gene are responsible for familial and sporadic interstitial lung disease (ILD). The consequences of such mutations on pulmonary surfactant composition and function are poorly understood. To determine the effects of a mutation in the SP-C gene on surfactant, we obtained lung tissue at the time of transplantation from a 14-mo-old infant with progressive ILD. An in-frame 9-bp deletion spanning codons 91-93 in Exon 3 of the SP-C gene was present on one allele; neither parent carried this deletion. SP-C mRNA was present in normal size and amount.