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1.
Anesthesiology ; 133(5): 1060-1076, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32796202

RESUMEN

BACKGROUND: Pulmonary atelectasis is frequent in clinical settings. Yet there is limited mechanistic understanding and substantial clinical and biologic controversy on its consequences. The authors hypothesize that atelectasis produces local transcriptomic changes related to immunity and alveolar-capillary barrier function conducive to lung injury and further exacerbated by systemic inflammation. METHODS: Female sheep underwent unilateral lung atelectasis using a left bronchial blocker and thoracotomy while the right lung was ventilated, with (n = 6) or without (n = 6) systemic lipopolysaccharide infusion. Computed tomography guided samples were harvested for NextGen RNA sequencing from atelectatic and aerated lung regions. The Wald test was used to detect differential gene expression as an absolute fold change greater than 1.5 and adjusted P value (Benjamini-Hochberg) less than 0.05. Functional analysis was performed by gene set enrichment analysis. RESULTS: Lipopolysaccharide-unexposed atelectatic versus aerated regions presented 2,363 differentially expressed genes. Lipopolysaccharide exposure induced 3,767 differentially expressed genes in atelectatic lungs but only 1,197 genes in aerated lungs relative to the corresponding lipopolysaccharide-unexposed tissues. Gene set enrichment for immune response in atelectasis versus aerated tissues yielded negative normalized enrichment scores without lipopolysaccharide (less than -1.23, adjusted P value less than 0.05) but positive scores with lipopolysaccharide (greater than 1.33, adjusted P value less than 0.05). Leukocyte-related processes (e.g., leukocyte migration, activation, and mediated immunity) were enhanced in lipopolysaccharide-exposed atelectasis partly through interferon-stimulated genes. Furthermore, atelectasis was associated with negatively enriched gene sets involving alveolar-capillary barrier function irrespective of lipopolysaccharide (normalized enrichment scores less than -1.35, adjusted P value less than 0.05). Yes-associated protein signaling was dysregulated with lower nuclear distribution in atelectatic versus aerated lung (lipopolysaccharide-unexposed: 10.0 ± 4.2 versus 13.4 ± 4.2 arbitrary units, lipopolysaccharide-exposed: 8.1 ± 2.0 versus 11.3 ± 2.4 arbitrary units, effect of lung aeration, P = 0.003). CONCLUSIONS: Atelectasis dysregulates the local pulmonary transcriptome with negatively enriched immune response and alveolar-capillary barrier function. Systemic lipopolysaccharide converts the transcriptomic immune response into positive enrichment but does not affect local barrier function transcriptomics. Interferon-stimulated genes and Yes-associated protein might be novel candidate targets for atelectasis-associated injury.


Asunto(s)
Inmunidad Celular/genética , Inmunidad Celular/inmunología , Atelectasia Pulmonar/genética , Atelectasia Pulmonar/inmunología , Transcriptoma/genética , Animales , Femenino , Mediciones del Volumen Pulmonar/métodos , Atelectasia Pulmonar/diagnóstico por imagen , Ovinos
2.
Am J Respir Cell Mol Biol ; 54(3): 410-23, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26252542

RESUMEN

Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum lumen protein localized to the secretory pathway. As a Ca2t-binding protein of 45 kDa (Cab45)/Rcn/ER Ca2t-binding protein of 55 kDa (ERC45)/calumenin (CREC) family member, Rcn3 is reported to function as a chaperone protein involved in protein synthesis and secretion; however, the biological role of Rcn3 is largely unknown. The results presented here, for the first time, depict an indispensable physiological role of Rcn3 in perinatal lung maturation by using an Rcn3 gene knockout mouse model. These mutant mice die immediately at birth owing to atelectasis-induced neonatal respiratory distress, although these embryos are produced with grossly normal development. This respiratory distress results from a failure of functional maturation of alveolar epithelial type II cells during alveogenesis. This immaturity of type II cells is associated with a dramatic reduction in surfactant protein A and D, a disruption in surfactant phospholipid homeostasis, and a disorder in lamellar body. In vitro studies further show that Rcn3 deficiency blunts the secretion of surfactant proteins and phospholipids from lung epithelial cells, suggesting a decrease in availability of surfactants for their surface activity. Collectively, these observations indicate an essential role of Rcn3 in perinatal lung maturation and neonatal respiratory adaptation as well as shed additional light on the mechanism of neonatal respiratory distress syndrome development.


Asunto(s)
Células Epiteliales Alveolares/metabolismo , Proteínas de Unión al Calcio/metabolismo , Pulmón/metabolismo , Atelectasia Pulmonar/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismo , Insuficiencia Respiratoria/metabolismo , Adaptación Fisiológica , Células Epiteliales Alveolares/patología , Animales , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , Línea Celular , Regulación del Desarrollo de la Expresión Génica , Predisposición Genética a la Enfermedad , Homocigoto , Pulmón/embriología , Pulmón/fisiopatología , Ratones Endogámicos C57BL , Ratones Noqueados , Morfogénesis , Mutación , Fenotipo , Fosfolípidos/metabolismo , Atelectasia Pulmonar/embriología , Atelectasia Pulmonar/genética , Atelectasia Pulmonar/fisiopatología , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Proteína D Asociada a Surfactante Pulmonar/genética , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Interferencia de ARN , Síndrome de Dificultad Respiratoria del Recién Nacido/embriología , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , Insuficiencia Respiratoria/embriología , Insuficiencia Respiratoria/genética , Insuficiencia Respiratoria/fisiopatología , Transducción de Señal , Transfección
3.
BMC Pediatr ; 13: 209, 2013 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-24344641

RESUMEN

BACKGROUND: Plastic bronchitis is an extremely rare disease characterized by the formation of tracheobronchial airway casts, which are composed of a fibrinous exudate with rubber-like consistency and cause respiratory distress as a result of severe airflow obstruction. Bronchial casts may be associated with congenital and acquired cardiopathies, bronchopulmonary diseases leading to mucus hypersecretion, and pulmonary lymphatic abnormalities. In recent years, however, there is growing evidence that plastic bronchitis can also be triggered by common respiratory tract infections and thereby cause atelectasis even in otherwise healthy children. CASE PRESENTATION: We report on 22-month-old monozygotic twins presenting with atelectasis triggered by a simple respiratory tract infection. The clinical, laboratory, and radiographic findings given, bronchial cast formation was suspected in both infants but could only be confirmed after bronchoscopy in the first case. Real-time polymerase chain reaction of the removed cast as well as nasal lavage fluid of both infants demonstrated strong positivity for human bocavirus. CONCLUSION: Our case report is the first to describe two simultaneously affected monozygotic twins and substantiates the hypothesis of a contributing genetic factor in the pathophysiology of this disease. In this second report related to human bocavirus, we show additional evidence that this condition can be triggered by a simple respiratory tract infection in previously healthy infants.


Asunto(s)
Bronquitis/complicaciones , Enfermedades en Gemelos , Bocavirus Humano/aislamiento & purificación , Infecciones por Parvoviridae/complicaciones , Atelectasia Pulmonar/etiología , Gemelos Monocigóticos , Bronquitis/diagnóstico , Bronquitis/virología , Broncoscopía , Exudados y Transudados , Humanos , Lactante , Masculino , Atelectasia Pulmonar/genética , Atelectasia Pulmonar/virología
4.
Nat Genet ; 10(3): 279-87, 1995 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-7670465

RESUMEN

We report the generation and characterization of mice lacking adenosine deaminase (ADA). In humans, absence of ADA causes severe combined immunodeficiency. In contrast, ADA-deficient mice die perinatally with marked liver-cell degeneration, but lack abnormalities in the thymus. The ADA substrates, adenosine and deoxyadenosine, are increased in ADA-deficient mice. Adenine deoxyribonucleotides are only modestly elevated, whereas S-adenosylhomocysteine hydrolase activity is reduced more than 85%. Consequently, the ratio of S-adenosylhomocysteine (AdoMet) to S-adenosyl homocysteine (AdoHcy) is reduced threefold in liver. We conclude that ADA plays a more critical role in murine than human fetal development. The murine liver pathology may be due to AdoHcy-mediated inhibition of AdoMet-dependent transmethylation reactions.


Asunto(s)
Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Intestino Delgado/patología , Hígado/patología , Atelectasia Pulmonar/genética , Animales , Animales Recién Nacidos , Secuencia de Bases , Muerte Celular , Cartilla de ADN/genética , Modelos Animales de Enfermedad , Desarrollo Embrionario y Fetal/genética , Desarrollo Embrionario y Fetal/fisiología , Femenino , Marcación de Gen , Homocigoto , Humanos , Masculino , Metilación , Ratones , Datos de Secuencia Molecular , Mutación , Embarazo , Purinas/metabolismo , Inmunodeficiencia Combinada Grave/etiología , Subgrupos de Linfocitos T/inmunología
5.
Mol Cell Biol ; 22(12): 4147-57, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12024028

RESUMEN

The mouse genome contains two Sim genes, Sim1 and Sim2. They are presumed to be important for central nervous system (CNS) development because they are homologous to the Drosophila single-minded (sim) gene, mutations in which cause a complete loss of CNS midline cells. In the mammalian CNS, Sim2 and Sim1 are coexpressed in the paraventricular nucleus (PVN). While Sim1 is essential for the development of the PVN (J. L. Michaud, T. Rosenquist, N. R. May, and C.-M. Fan, Genes Dev. 12:3264-3275, 1998), we report here that Sim2 mutant has a normal PVN. Analyses of the Sim1 and Sim2 compound mutants did not reveal obvious genetic interaction between them in PVN histogenesis. However, Sim2 mutant mice die within 3 days of birth due to lung atelectasis and breathing failure. We attribute the diminished efficacy of lung inflation to the compromised structural components surrounding the pleural cavity, which include rib protrusions, abnormal intercostal muscle attachments, diaphragm hypoplasia, and pleural mesothelium tearing. Although each of these structures is minimally affected, we propose that their combined effects lead to the mechanical failure of lung inflation and death. Sim2 mutants also develop congenital scoliosis, reflected by the unequal sizes of the left and right vertebrae and ribs. The temporal and spatial expression patterns of Sim2 in these skeletal elements suggest that Sim2 regulates their growth and/or integrity.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Proteínas Represoras/genética , Respiración/genética , Factores de Transcripción/genética , Animales , Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Sistema Nervioso Central/crecimiento & desarrollo , Sistema Nervioso Central/metabolismo , Diafragma/anomalías , Cara/embriología , Femenino , Pulmón/patología , Masculino , Mesodermo , Ratones , Ratones Mutantes , Obesidad/genética , Núcleo Hipotalámico Paraventricular/crecimiento & desarrollo , Atelectasia Pulmonar/genética , Atelectasia Pulmonar/fisiopatología , Proteínas Represoras/metabolismo , Costillas/anomalías , Columna Vertebral/anomalías , Factores de Transcripción/metabolismo
7.
Cell Reprogram ; 17(5): 360-7, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26393896

RESUMEN

Cloned calves produced by somatic cell nuclear transfer frequently suffer alveolar collapse as newborns. To study the underlying pathophysiological mechanisms responsible for this phenomenon, the expression profiles of numerous genes involved in lung development need to be investigated. Quantitative real-time PCR is commonly adopted in gene expression analysis. However, selection of an appropriate reference gene for normalization is critical for obtaining reliable and accurate results. Seven housekeeping genes-ß-glucuronidase (GUSB), phosphoglycerate kinase 1 (PGK1), ß-2-microglobolin (B2M), peptidylprolyl isomerase A (PPIA), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), TATA-box binding protein (TBP), and 5.8S ribosomal RNA (5.8S rRNA)-were selected and evaluated as candidates. Their gene expression levels in the collapsed lungs of deceased neonate cloned calves and normal lung derived from normal calves were assessed. The ranking of gene expression stability was estimated by the geNorm, NormFinder, and BestKeeper programs. 5.8S rRNA and PPIA were determined to be the most stable reference genes by geNorm and BestKeeper, whereas the combination of GAPDH and TBP was suggested as reference genes by NormFinder. Taking these results into account, we conclude that 5.8S rRNA and PPIA could be the most reliable reference genes for studying the genes involved in alveolar collapse. Moreover, 5.8S rRNA could be represented as a uniform reference gene in similar cases.


Asunto(s)
Enfermedades de los Bovinos/genética , Perfilación de la Expresión Génica/normas , Genes Esenciales , Pulmón/metabolismo , Técnicas de Transferencia Nuclear , Atelectasia Pulmonar/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/normas , Animales , Bovinos , Enfermedades de los Bovinos/metabolismo , Expresión Génica , Atelectasia Pulmonar/metabolismo , Estándares de Referencia
8.
FEBS Lett ; 467(1): 7-11, 2000 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-10664446

RESUMEN

In order to address the biological function of GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST-1), we disrupted the NDST-1 gene by homologous recombination in mouse embryonic stem cells. The NDST-1 null mice developed respiratory distress and atelectasis that subsequently caused neonatal death. Morphological examination revealed type II pneumocyte immaturity, which was characterized by an increased glycogen content and a reduced number of lamellar bodies and microvilli. Biochemical analysis further indicated that both total phospholipids and disaturated phosphatidylcholine were reduced in the mutant lung. Our data revealed that NDST-1 was essential for the maturation of type II pneumocytes and its inactivation led to a neonatal respiratory distress syndrome.


Asunto(s)
Amidohidrolasas/genética , Eliminación de Gen , Pulmón/patología , Pulmón/fisiopatología , Síndrome de Dificultad Respiratoria del Recién Nacido/enzimología , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Sulfotransferasas/genética , Animales , Animales Recién Nacidos , Diferenciación Celular , Células Epiteliales/patología , Humanos , Recién Nacido , Pulmón/química , Pulmón/embriología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica , Fosfatidilcolinas/análisis , Fosfolípidos/análisis , Atelectasia Pulmonar/genética , Atelectasia Pulmonar/mortalidad , Atelectasia Pulmonar/patología , Atelectasia Pulmonar/fisiopatología , Surfactantes Pulmonares/análisis , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología
9.
Ital J Pediatr ; 39: 9, 2013 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-23391190

RESUMEN

Glycogenosis type II (Pompe disease) is a rare autosomal recessive genetic disorder caused by mutations in the gene encoding the lysosomal enzyme acid α-glucosidase. The classic form is characterized by severe cardiac involvement, generalized hypotonia and exitus early in life. Presenting symptoms and signs of the disease may be neglected or underestimated, thus delaying the diagnosis. Respiratory manifestations mainly occur because of respiratory muscle weakness. However, additional mechanisms can favor the development of pulmonary complications that result in fatal respiratory failure. We herein describe a case of an infant with glycogenosis type II presenting with hepatomegaly and hypertransaminasemia, who rapidly developed fatal lung disease.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Mutación , Atelectasia Pulmonar/genética , Insuficiencia Respiratoria/genética , Transaminasas/genética , alfa-Glucosidasas/genética , Biomarcadores/sangre , Cardiomegalia/genética , Resultado Fatal , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/terapia , Hepatomegalia/genética , Humanos , Lactante , Hipotonía Muscular/genética , Transaminasas/sangre
11.
Acta Paediatr ; 93(3): 414-6, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15124850

RESUMEN

UNLABELLED: The aim of this pilot study was to obtain information on the value of MRI in the follow-up of atelectasis and pneumonic infiltrates in cystic fibrosis (CF). Six patients aged 5-15 y were initially examined using chest X-ray and magnetic resonance imaging (MRI). Both methods provided identical information. During follow-up, MRI proved suitable to monitor pulmonary complications. CONCLUSION: MRI of the lung is feasible and valuable in the follow-up of atelectasis and pulmonary infiltrates in CF.


Asunto(s)
Fibrosis Quística/complicaciones , Imagen por Resonancia Magnética , Atelectasia Pulmonar/diagnóstico , Enfermedad Aguda , Adolescente , Niño , Preescolar , Estudios de Seguimiento , Humanos , Proyectos Piloto , Neumonía/diagnóstico , Neumonía/etiología , Atelectasia Pulmonar/genética
12.
J Hered ; 77(2): 109-13, 1986.
Artículo en Inglés | MEDLINE | ID: mdl-3711636

RESUMEN

A syndrome including deficient linear, endochondral, and radial bone growth associated with severe cervico-thoracic lordosis, decreased intrathoracic volume, atelectasis, and early death has been noted in mice possessing the phenotypes of the recessive mutant genes pallid (pa) and wellhaarig (we) as the result of recombination of chromosome 2 between these genes. The syndrome is not seen in the parental strains, which are homozygous for the chromosomal segment containing one or the other gene (pa +/pa + or + we/+ we), nor in the intercross mice heterozygous for both genes in the trans configuration (pa+/+we). The abnormal offspring appeared randomly in the breeding colony with no F1 breeding pair producing more than one pa we mouse. These observations rule out the presence of a mutant gene, fixed or unfixed, as an explanation for this syndrome. We hypothesize that the syndrome is the result of the complementary action of the genes or the chromosomal segments containing the genes pa and we or weBkr. The posited synergism is further supported by the finding that we, which functions as a recessive gene in mice of the pa/+ genotype, appears to function as a dominant gene in mice possessing the pa/pa genotype.


Asunto(s)
Huesos/anomalías , Ratones Mutantes/genética , Animales , Mapeo Cromosómico , Cruzamientos Genéticos , Femenino , Genes Dominantes , Genes Recesivos , Masculino , Ratones , Ratones Endogámicos C57BL/genética , Fenotipo , Embarazo , Atelectasia Pulmonar/etiología , Atelectasia Pulmonar/genética , Recombinación Genética , Síndrome
13.
Pediatrie ; 37(8): 573-8, 1982 Dec.
Artículo en Francés | MEDLINE | ID: mdl-6985080

RESUMEN

The authors report two cases of immotile cilia syndrome occurring in two children without situs inversus. The two boys, 3 and 7 years old, had bronchiectasis, chronic sinusitis and recurrent upper airway infections. In the siblings, we found Kartagener's syndrome (sister of the first boy, and two sibs of the second). The diagnosis in the 2 cases was performed by study of ciliary motion in bronchial brushing. Ultrastructural examination of biopsies from bronchial mucosa showed specific defects of the axoneme.


Asunto(s)
Bronquiectasia/diagnóstico , Cilios/fisiopatología , Atelectasia Pulmonar/diagnóstico , Adolescente , Bronquiectasia/genética , Niño , Preescolar , Cilios/ultraestructura , Femenino , Humanos , Síndrome de Kartagener/complicaciones , Masculino , Atelectasia Pulmonar/genética , Síndrome
14.
Am J Respir Crit Care Med ; 169(5): 634-7, 2004 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-14982824

RESUMEN

Primary ciliary dyskinesia is an autosomal recessive disorder characterized by chronic upper and lower respiratory tract symptoms. We report the diagnosis of primary ciliary dyskinesia associated with a circular ciliary beat pattern in three siblings. This beat pattern is consistent with a ciliary transposition defect, where a peripheral microtubule doublet is transposed to the center of the ciliary axoneme to replace the absent central microtubule pair. However, in these siblings, ultrastructural analysis of the cilia revealed an absence of the central microtubule pair only. This variant of transposition with a circular ciliary beat pattern has not been described previously. In addition, this defect, together with the transposition defect, may help explain the mechanism of the circular beat pattern and also the absence of situs inversus in these patients.


Asunto(s)
Síndrome de Kartagener/genética , Microtúbulos/ultraestructura , Árabes/genética , Biopsia , Bronquiectasia/genética , Niño , Consanguinidad , Tos/genética , Diagnóstico Diferencial , Femenino , Genes Recesivos/genética , Humanos , Lactante , Síndrome de Kartagener/complicaciones , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/fisiopatología , Masculino , Microscopía Electrónica , Depuración Mucociliar , Atelectasia Pulmonar/genética , Infecciones del Sistema Respiratorio/genética , Rinitis/genética , Situs Inversus/genética , Tomografía Computarizada por Rayos X , Emiratos Árabes Unidos
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