Showing papers on "Alveolar capillary dysplasia published in 2014"
TL;DR: FoxF1 is required for the formation of embryonic vasculature by regulating endothelial genes critical for vascular development and vascular endothelial growth factor signaling.
Abstract: Rationale:Inactivating mutations in the Forkhead Box transcription factor F1 (FOXF1) gene locus are frequently found in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a lethal congenital disorder, which is characterized by severe abnormalities in the respiratory, cardiovascular, and gastrointestinal systems. In mice, haploinsufficiency of the Foxf1 gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal, and gall bladder morphogenesis. Objective:Although FOXF1 is expressed in multiple mesenchyme-derived cell types, cellular origins and molecular mechanisms of developmental abnormalities in FOXF1-deficient mice and patients with alveolar capillary dysplasia with misalignment of pulmonary veins remain uncharacterized because of lack of mouse models with cell-restricted inactivation of the Foxf1 gene. In the present study, the role of FOXF1 in endothelial cells was examined using a conditional knockout approach. Methods and Results:A novel mous...
109 citations
TL;DR: The use of a paracorporeal lung assist device successfully supported 4 patients to recovery, lung transplantation, or past the average wait time for pediatric donor lungs (27 days).
69 citations
TL;DR: Normal pulmonary vascular development is described, and the lines of research that seem to be very promising for elucidating the molecular pathways involved in the origin of congenital pulmonary vascular disease are indicated.
Abstract: Pulmonary vascular diseases of the newborn comprise a wide range of pathological conditions with developmental abnormalities in the pulmonary vasculature. Clinically, pulmonary arterial hypertension (PH) is characterized by persistent increased resistance of the vasculature and abnormal vascular response. The classification of PH is primarily based on clinical parameters instead of morphology and distinguishes five groups of PH. Congenital lung anomalies, such as alveolar capillary dysplasia (ACD) and PH associated with congenital diaphragmatic hernia (CDH), but also bronchopulmonary dysplasia (BPD), are classified in group three. Clearly, tight and correct regulation of pulmonary vascular development is crucial for normal lung development. Human and animal model systems have increased our knowledge and make it possible to identify and characterize affected pathways and study pivotal genes. Understanding of the normal development of the pulmonary vasculature will give new insights in the origin of the spectrum of rare diseases, such as CDH, ACD, and BPD, which render a significant clinical problem in neonatal intensive care units around the world. In this review, we describe normal pulmonary vascular development, and focus on four diseases of the newborn in which abnormal pulmonary vascular development play a critical role in morbidity and mortality. In the future perspective, we indicate the lines of research that seem to be very promising for elucidating the molecular pathways involved in the origin of congenital pulmonary vascular disease.
47 citations
TL;DR: RNAi‐mediated knock‐down of LINC01081 in normal fetal lung fibroblasts showed that this lncRNA positively regulates FOXF1 transcript level, further indicating that decrease in LINC 01081 expression can contribute to development of ACDMPV.
Abstract: Position effects due to disruption of distant cis-regulatory regions have been reported for over 40 human gene loci; however, the underlying mechanisms of long-range gene regulation remain largely unknown. We report on two patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) caused by overlapping genomic deletions that included a distant FOXF1 transcriptional enhancer mapping 0.3 Mb upstream to FOXF1 on 16q24.1. In one patient with atypical late-onset ACDMPV, a ∼1.5 Mb deletion removed the proximal 43% of this enhancer, leaving the lung-specific long non-coding RNA (lncRNA) gene LINC01081 intact. In the second patient with severe neonatal-onset ACDMPV, an overlapping ∼194 kb deletion disrupted LINC01081. Both deletions arose de novo on maternal copy of the chromosome 16, supporting the notion that FOXF1 is paternally imprinted in the human lungs. RNAi-mediated knock-down of LINC01081 in normal fetal lung fibroblasts showed that this lncRNA positively regulates FOXF1 transcript level, further indicating that decrease in LINC01081 expression can contribute to development of ACDMPV.
46 citations
TL;DR: 3-dimensional reconstruction of ACD/MPV lung tissue is used to report that the veins in MPV are intrapulmonary shunt vessels, and speculate that MPV contributes to the poor prognosis.
38 citations
TL;DR: Comparison of transcriptomes of human ACDMPV lungs with control lungs using expression arrays found that several genes and pathways involved in lung development, angiogenesis, and in pulmonary hypertension development, were deregulated.
Abstract: Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a developmental disorder of the lungs, primarily affecting their vasculature. FOXF1 haploinsufficiency due to heterozygous genomic deletions and point mutations have been reported in most patients with ACDMPV. The majority of mice with heterozygous loss-of-function of Foxf1 exhibit neonatal lethality with evidence of pulmonary hemorrhage in some of them. By comparing transcriptomes of human ACDMPV lungs with control lungs using expression arrays, we found that several genes and pathways involved in lung development, angiogenesis, and in pulmonary hypertension development, were deregulated. Similar transcriptional changes were found in lungs of the postnatal day 0.5 Foxf1+/- mice when compared to their wildtype littermate controls; 14 genes, COL15A1, COL18A1, COL6A2, ESM1, FSCN1, GRINA, IGFBP3, IL1B, MALL, NOS3, RASL11B, MATN2, PRKCDBP, and SIRPA, were found common to both ACDMPV and Foxf1 heterozygous lungs. Our results advance knowledge toward understanding of the molecular mechanism of ACDMPV, lung development, and its vasculature pathology. These data may also be useful for understanding etiologies of other lung disorders, e.g. pulmonary hypertension, bronchopulmonary dysplasia, or cancer.
30 citations
TL;DR: The SP-C abnormality was most prevalent, andSP-B deficiency was rare in Japanese infants with hereditary ILD, and the 17 bronchoalveolar lavage or tracheal aspirates contained enough SP-B protein.
Abstract: Genetic variations associated with interstitial lung diseases (ILD) have not been extensively studied in Japanese infants. Forty-three infants with unexplained lung dysfunction were studied. All 43, 22, and 17 infants underwent analyses of surfactant protein (SP)-C gene (SFTPC) and ATP-binding cassette A3 gene (ABCA3), SP-B gene (SFTPB), and SP-B western blotting, respectively. Two and four underwent assessment of granulocyte macrophage colony-stimulating factor–stimulating phosphorylation of signal transducer and activator of transcription-5 (pSTAT-5) and analyses of FOXF1 gene (FOXF1), respectively. ILD were diagnosed clinically in nine infants: four, three, and two had interstitial pneumonitis, hereditary pulmonary alveolar proteinosis (hPAP), and alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), respectively. Genetic variations considered responsible were detected in six (67%) of the nine infants with ILD: three with hPAP (SFTPC p.Leu45Arg and p.Gln145fs, and ABCA3 p.Arg1583Trp/p.Val1495CysfsX21), two with interstitial pneumonitis (SFTPC p.Lys63Glu and p.Ser72Asn/p.Gly100Ala), and one with ACD/MPV (FOXF1 p.Leu300ArgfsX79). None showed SFTPB mutations or defects in pSTAT-5. The 17 bronchoalveolar lavage or tracheal aspirates contained enough SP-B protein. The SP-C abnormality was most prevalent, and SP-B deficiency was rare in Japanese infants with hereditary ILD.
16 citations
TL;DR: The clinical course of a neonate with refractory pulmonary hypertension diagnosed with ACD/MPV, aortic coarctation and other not previously reported associated malformations are described.
Abstract: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal cause of refractory pulmonary hypertension of the newborn. We describe the clinical course of a neonate with refractory pulmonary hypertension diagnosed with ACD/MPV, aortic coarctation and other not previously reported associated malformations.
6 citations
TL;DR: A case of alveolar capillary dysplasia with misaligned pulmonary veins is reported, which can affect the decision to use invasive and likely ineffective therapy such as extracorporeal membrane oxygenation.
6 citations
TL;DR: A case of quickly fatal congenital lung dysplasia in a full-term infant is presented and underlines the necessity to suspect this disease in a newborn suffering from severe and refractory respiratory distress.
Abstract: Acinar dysplasia congenital alveolar dysplasia and alveolar capillary dysplasia with misalignment of pulmonary veins belong to the diffuse developmental disorders (congenital lung dysplasia), very rare fatal disorders of infancy that occur early in lung development. A case of quickly fatal congenital lung dysplasia in a full-term infant is presented and underlines the necessity to suspect this disease in a newborn suffering from severe and refractory respiratory distress.
6 citations
01 Jan 2014
TL;DR: Deiros et al. as discussed by the authors described the clinical course of a neonate with refractory pulmonary hypertension diagnosed with ACD/MPV, aortic coarctation and other not previously reported associated malformations.
Abstract: , L Deiros and MJ Del CerroAlveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal cause of refractory pulmonaryhypertension of the newborn. We describe the clinical course of a neonate with refractory pulmonary hypertension diagnosed withACD/MPV, aortic coarctation and other not previously reported associated malformations.Journal of Perinatology (2014) 34, 795–797; doi:10.1038/jp.2014.94INTRODUCTIONAlveolar capillary dysplasia with misalignment of the pulmonaryveins (ACD/MPV) is a rare and lethal cause of refractory pulmonaryhypertension of the newborn.
TL;DR: A patient is described with alveolar capillary dysplasia, multiple congenital anomalies, a novel genetic mutation and previously undocumented airway findings on bronchoscopy, which may help diagnose this rare disorder in neonates with hypoxemic respiratory failure.
Abstract: Alveolar capillary dysplasia is a rare and fatal disease of newborn infants. Here we describe a patient with alveolar capillary dysplasia, multiple congenital anomalies, a novel genetic mutation and previously undocumented airway findings on bronchoscopy. Knowledge of these associations may help diagnose this rare disorder in neonates with hypoxemic respiratory failure.
01 Jan 2014
TL;DR: The main events in lung development include branching morphogenesis to form the bronchial tree and formation and expansion of the air–blood barrier for gas exchange and the transition from an aqueous intrauterine environment to breathing air requires a mature surfactant to reduce surface tension.
Abstract: The main events in lung development include branching morphogenesis to form the bronchial tree and formation and expansion of the air–blood barrier for gas exchange. Many pediatric lung diseases and malformations can be understood through the examination of normal development. The main factors influencing airway branching are signaling from the mesenchyme to the epithelium and intraluminal fluid pressure. Defects in these processes can lead to pulmonary hypoplasia as well as tracheoesophageal fistulas, bronchogenic cysts, pulmonary sequestrations, and congenital pulmonary airway malformations. Air–blood barrier formation requires proliferation of capillaries, a decrease in the mesenchyme, and differentiation of type I and II pneumocytes. Extreme premature birth is a risk factor for defects in these processes and can lead to bronchopulmonary dysplasia. The transition from an aqueous intrauterine environment to breathing air requires a mature surfactant to reduce surface tension. Multiple genetic defects in surfactant proteins and metabolism have been recently described.
TL;DR: Early lung biopsy for a histological diagnosis allows expensive and ineffective treatment to be avoided and can be performed with low risk and high-diagnostic yield for alveolar capillary dysplasia.
Abstract: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, fatal, congenital lung disorder involving abnormal development of the capillary vascular system around the alveoli of the lungs, which clinically presents as persistent pulmonary hypertension of the newborn (PPHN) refractory to treatment. It has been linked to the gene FOXF1 on chromosome 16q24.1–q24.2. Histopathological examination by lung biopsy is the gold standard for diagnosis. We present four cases of ACD/MPV who were referred for ECMO support with a diagnosis of PPHN with no apparent congenital anomalies. All the newborns had an overwhelming course, with PPHN and hypoxemia refractory to treatment. The diagnosis of ACD/MPV was established by ante-mortem lung biopsy in all cases. Intensive care treatment was withdrawn post diagnosis, with none of the four surviving. Early lung biopsy for a histological diagnosis allows expensive and ineffective treatment to be avoided. Lung biopsy can be performed with low risk and high-diagnostic yield for alveolar capillary dysplasia.
TL;DR: Genetic defects affecting the FOXF1 pathway affect the mesenchymal, endothelial and epithelial cross-talk leading to lung developmental disruption, pulmonary hypertension and hypoxic respiratory failure.
Abstract: Background/aims Alveolar capillary dysplasia (ACD) is characterised by pulmonary veins misalignment, capillary paucity and alveolar misdevelopment, and caused by FOXF1 mutations only in 40% of cases. Objectives were 1. to identify known and new gene defects and 2. to correlate them with molecular/cellular mechanisms. Methods We recruited a cohort of 23 pathology-confirmed cases. When DNA was available, genome-wide copy number variation was analysed through Array Comparative Genomic Hybridization (aCGH). Mutations were tested by direct sequencing of FOXF1 and candidate genes identified by aCGH; Molecular pathways were analysed by multi-channel immunofluorescence microscopy of ACD cases compared to human fetal/neonatal lung tissue at various development stages. Results Genomic deletions or mutations were identified in 57% of tested cases. Besides FOXF1, two of the genes involved stand out as potential candidates: MEOX2 and TBX4. ACD cases showed a markedly decreased expression of c-kit, a marker expressed in pulmonary small arteries and capillaries in fetal lung controls. In normal fetal lungs FOXF1 and TBX4 were prevalently expressed at the mesenchymal-epithelial border, and MEOX2 in pulmonary vascular smooth muscle cells (PVSMC). Their expression pattern and intensity were altered in all ACD cases, indicating that decreased FOXF-1 and/or its downstream transcription factor TBX4 disrupt lung micro vessel formation and homing to alveolar epithelium, and that a similar phenotype may derive from dysregulated PVSMC proliferation and angiogenesis related to MEOX2 insufficiency. Conclusion Genetic defects affecting the FOXF1 pathway affect the mesenchymal, endothelial and epithelial cross-talk leading to lung developmental disruption, pulmonary hypertension and hypoxic respiratory failure.
TL;DR: Think about chILD if a child has chronic, unremitting tachypnoea, retractions, crackles and failure to thrive, and be alert to comorbidities, complications of disease or treatment, or signs of recurrent or worsening lung disease.
Abstract: Definition Childhood interstitial lung disease (chILD) includes a range of rare disorders of the lung parenchyma (and, sometimes, airways) that have certain clinical features in common Specific conditions within chILD include surfactant protein B or C deficiency, alveolar capillary dysplasia with misalignment of lung veins, pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia, hypersensitivity pneumonitis, eosinophilic pneumonia, lymphocytic interstitial pneumonia, alveolar proteinosis, granulomatosis with polyangiitis, sarcoidosis, lung alveolar proteinosis, and Langerhans’ cell histiocytosis chILD may complicate other disorders including inflammatory bowel disease and liver disease In many children with chILD, no specific diagnosis can be made Key messages Think about chILD if a child has chronic, unremitting tachypnoea, retractions, crackles and failure to thrive Symptoms of early chILD are very unspecific and may be missed unless there is a high level of suspicion Refer the patient to a specialist centre in paediatric pulmonology Follow your patient longitudinally in collaboration with the reference centre, and be alert to comorbidities, complications of disease or treatment, or signs of recurrent or worsening lung disease