Surfactant Protein-C Promoter Variants Associated With Neonatal Respiratory Distress Syndrome Reduce Transcription

Wambach, Jennifer A.; Yang, Ping; Wegner, Daniel; An, Ping; Hackett, Brian P.; Cole, F. Sessions; Hamvas, Aaron

doi:10.1203/pdr.0b013e3181eb5d68

Cited by 37 publications

(15 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A smaller group of individuals have reduced SP-C levels and decreased mRNA expression without the generation of aberrant forms of the proprotein. Specifically, a single study identified three infants with respiratory distress syndrome associated with mutations in the SFTPC promoter that decreased expression without introducing any distortion of SP-C biosynthesis (7). Together, these reports suggest a compound disease pathogenesis from both the absence of mature SP-C and/or from cellular stress induced by malformed proSP-C.…”

Section: Discussionmentioning

confidence: 93%

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Glasser

Maxfield²,

Ruetschilling³

et al. 2013

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Pulmonary surfactant protein-C (SP-C) gene-targeted mice (Sftpc 2/2 ) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc 1/1 and Sftpc 2/2 mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc 2/2 mice at 3 and 5 days after the final dose. Compared with Sftpc 1/1 mice, inflammatory injury persisted in the lungs of Sftpc 2/2 mice 30 days after the final LPS challenge. Sftpc 2/2 mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc 2/2 type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc 1/1 cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C-containing clinical surfactant extract (Survanta) or SP-C/phospholipid vesicles blocked LPS signaling through the LPS receptor (Toll-like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation.Keywords: surfactant protein-C; LPS; lung inflammation; type II cells; Toll-like receptor 4Surfactant protein-C (SP-C) is an abundant 3.5-kD surfactantassociated protein expressed and secreted by alveolar type II epithelial cells. The mature airspace form of SP-C is highly hydrophobic and palmitoylated at adjacent amino terminal cysteine residues (1). Mutations in the gene encoding human SP-C (SFTPC) have been shown to cause familial interstitial lung disease (ILD). Affected individuals express an altered proSP-C, leading to reduced levels of mature SP-C in the airspace (2-4). SP-C deficiencies without detectable mutations in the protein-coding region of SFTPC or due to promoter mutations have also been reported, and represent a true null condition (5-7). These individuals also develop ILD, including idiopathic pulmonary fibrosis (IPF). SP-C deficiency-related disease may arise as an acute childhood or as a late-onset disease in adulthood (3). Because SP-C is expressed exclusively in alveolar type II cells, the associated ILD/idiopathic pulmonary fibrosis presumably originates from a primary defect in the epithelium. SP-C deficiency increases susceptibility to viral-or bacterial-induced exacerbations in affected children (5,6,(8)(9)(10). SP-C-deficient mice (Sftpc 2/2 ) developed a strain-specific pulmonary phenotype with age that was similar to the human disease (11). Sftpc 2/2 mice were more susceptible to challenge with ...

show abstract

Section: Discussionmentioning

confidence: 93%

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Glasser

Maxfield²,

Ruetschilling³

et al. 2013

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…DNA was isolated from blood (n = 180), frozen lung tissue (n = 4), and saliva (n = 1) using commercially available kits as previously described (15,20). Sequence analysis of the coding exons and flanking introns was performed for all subjects as previously described (15,20).…”

Section: Mutational Analysismentioning

confidence: 99%

“…Sequence analysis of the coding exons and flanking introns was performed for all subjects as previously described (15,20).…”

Section: Mutational Analysismentioning

confidence: 99%

Genotype–Phenotype Correlations for Infants and Children with ABCA3 Deficiency

Wambach

Casey

Fishman

et al. 2014

Am J Respir Crit Care Med

Self Cite

184

223

View full text Add to dashboard Cite

Rationale: Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease. Most ABCA3 mutations are private.Objectives: To determine genotype-phenotype correlations for recessive ABCA3 mutations.Methods: We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as "null," whereas missense, predicted splice site mutations, and insertion/deletions were classified as "other." We compared age of presentation and outcomes for the three genotypes: null/null, null/other, and other/other. Measurements and Main Results:We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared with 75% of infants with null/ other or other/other genotypes (P = 0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared with 62% of the null/other and other/other children (P , 0.0001).Conclusions: Genotype-phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.

show abstract

“…SP-C related disease can occur as acute postnatal respiratory distress or with slow onset that is identified as respiratory insufficiency during childhood through adulthood [2,3]. The molecular pathogenesis of SP-C related lung disease includes loss of gene expression without defined mutations, decreased expression from non-coding promoter mutations, and most commonly mutations in the SP-C coding gene ( SFTPC ) [4-6]. The SFTPC mutations have distinct consequences, altering mRNA splicing, proprotein structure, protein expression, or processing.…”

Section: Introductionmentioning

confidence: 99%

Genetic replacement of surfactant protein-C reduces respiratory syncytial virus induced lung injury

et al. 2013

View full text Add to dashboard Cite

BackgroundIndividuals with deficiencies of pulmonary surfactant protein C (SP-C) develop interstitial lung disease (ILD) that is exacerbated by viral infections including respiratory syncytial virus (RSV). SP-C gene targeted mice (Sftpc -/-) lack SP-C, develop an ILD-like disease and are susceptible to infection with RSV.MethodsIn order to determine requirements for correction of RSV induced injury we have generated compound transgenic mice where SP-C expression can be induced on the Sftpc -/- background (SP-C/Sftpc -/-) by the administration of doxycycline (dox). The pattern of induced SP-C expression was determined by immunohistochemistry and processing by Western blot analysis. Tissue and cellular inflammation was measured following RSV infection and the RSV-induced cytokine response of isolated Sftpc +/+ and -/- type II cells determined.ResultsAfter 5 days of dox administration transgene SP-C mRNA expression was detected by RT-PCR in the lungs of two independent lines of bitransgenic SP-C/Sftpc -/- mice (lines 55.3 and 54.2). ProSP-C was expressed in the lung, and mature SP-C was detected by Western blot analysis of the lavage fluid from both lines of SP-C/Sftpc -/- mice. Induced SP-C expression was localized to alveolar type II cells by immunostaining with an antibody to proSP-C. Line 55.3 SP-C/Sftpc -/- mice were maintained on or off dox for 7 days and infected with 2.6x107 RSV pfu. On day 3 post RSV infection total inflammatory cell counts were reduced in the lavage of dox treated 55.3 SP-C/Sftpc -/- mice (p = 0.004). The percentage of neutrophils was reduced (p = 0.05). The viral titers of lung homogenates from dox treated 55.3 SP-C/Sftpc -/- mice were decreased relative to 55.3 SP-C/Sftpc -/- mice without dox (p = 0.01). The cytokine response of Sftpc -/- type II cells to RSV was increased over that of Sftpc +/+ cells.ConclusionsTransgenic restoration of SP-C reduced inflammation and improved viral clearance in the lungs of SP-C deficient mice. The loss of SP-C in alveolar type II cells compromises their response to infection. These findings show that the restoration of SP-C in Sftpc -/- mice in response to RSV infection is a useful model to determine parameters for therapeutic intervention.

show abstract

Surfactant Protein-C Promoter Variants Associated With Neonatal Respiratory Distress Syndrome Reduce Transcription

Cited by 37 publications

References 35 publications

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Genotype–Phenotype Correlations for Infants and Children with ABCA3 Deficiency

Genetic replacement of surfactant protein-C reduces respiratory syncytial virus induced lung injury

Contact Info

Product

Resources

About