RESUMEN
Type 3 innate lymphoid cells (ILC3s) are critical for lung defense against bacterial pneumonia in the neonatal period, but the signals that guide pulmonary ILC3 development remain unclear. Here, we demonstrated that pulmonary ILC3s descended from ILC precursors that populated a niche defined by fibroblasts in the developing lung. Alveolar fibroblasts produced insulin-like growth factor 1 (IGF1), which instructed expansion and maturation of pulmonary ILC precursors. Conditional ablation of IGF1 in alveolar fibroblasts or deletion of the IGF-1 receptor from ILC precursors interrupted ILC3 biogenesis and rendered newborn mice susceptible to pneumonia. Premature infants with bronchopulmonary dysplasia, characterized by interrupted postnatal alveolar development and increased morbidity to respiratory infections, had reduced IGF1 concentrations and pulmonary ILC3 numbers. These findings indicate that the newborn period is a critical window in pulmonary immunity development, and disrupted lung development in prematurely born infants may have enduring effects on host resistance to respiratory infections.
Asunto(s)
Inmunidad Innata , Factor I del Crecimiento Similar a la Insulina/metabolismo , Pulmón/inmunología , Linfocitos/citología , Células Epiteliales Alveolares/metabolismo , Animales , Animales Recién Nacidos , Displasia Broncopulmonar/inmunología , Diferenciación Celular , Proliferación Celular , Susceptibilidad a Enfermedades/inmunología , Humanos , Recién Nacido , Recien Nacido Prematuro , Factor I del Crecimiento Similar a la Insulina/deficiencia , Interleucinas/metabolismo , Pulmón/citología , Pulmón/crecimiento & desarrollo , Linfocitos/metabolismo , Ratones , Neumonía/inmunología , Proteína de la Leucemia Promielocítica con Dedos de Zinc/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal , Interleucina-22RESUMEN
Variable lung disease was documented in 2 infants with heterozygous TBX4 mutations; their clinical presentations, pathology, and outcomes were distinct. These findings demonstrate that TBX4 gene mutations are associated with neonatal respiratory failure and highlight the wide spectrum of clinicopathological outcomes that have implications for patient diagnosis and management.
Asunto(s)
Mutación/genética , Insuficiencia Respiratoria/genética , Insuficiencia Respiratoria/patología , Proteínas de Dominio T Box/genética , Femenino , Humanos , Recién Nacido , MasculinoRESUMEN
BACKGROUND: Premature infants often require oxygen supplementation and, therefore, are exposed to oxidative stress. Following oxygen exposure, preterm infants frequently develop chronic lung disease and have a significantly increased risk of asthma. OBJECTIVE: We sought to identify the underlying mechanisms by which neonatal hyperoxia promotes asthma development. METHODS: Mice were exposed to neonatal hyperoxia followed by a period of room air recovery. A group of mice was also intranasally exposed to house dust mite antigen. Assessments were performed at various time points for evaluation of airway hyperresponsiveness, eosinophilia, mucus production, inflammatory gene expression, and TH and group 2 innate lymphoid cell (ILC2) responses. Sera from term- and preterm-born infants were also collected and levels of IL-33 and type 2 cytokines were measured. RESULTS: Neonatal hyperoxia induced asthma-like features including airway hyperresponsiveness, mucus hyperplasia, airway eosinophilia, and type 2 pulmonary inflammation. In addition, neonatal hyperoxia promoted allergic TH responses to house dust mite exposure. Elevated IL-33 levels and ILC2 responses were observed in the lungs most likely due to oxidative stress caused by neonatal hyperoxia. IL-33 receptor signaling and ILC2s were vital for the induction of asthma-like features following neonatal hyperoxia. Serum IL-33 levels correlated significantly with serum levels of IL-5 and IL-13 but not IL-4 in preterm infants. CONCLUSIONS: These data demonstrate that an axis involving IL-33 and ILC2s is important for the development of asthma-like features following neonatal hyperoxia and suggest therapeutic potential for targeting IL-33, ILC2s, and oxidative stress to prevent and/or treat asthma development related to prematurity.
Asunto(s)
Asma/inmunología , Hiperoxia/inmunología , Interleucina-33/inmunología , Linfocitos/inmunología , Animales , Animales Recién Nacidos , Asma/sangre , Línea Celular , Preescolar , Células Epiteliales/metabolismo , Femenino , Humanos , Hiperoxia/sangre , Lactante , Recién Nacido , Recien Nacido Prematuro , Interleucina-33/sangre , Ratones Endogámicos C57BL , Ratones Noqueados , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Many studies have investigated the source and role of epithelial progenitors during lung development; such information is limited for fibroblast populations and their complex role in the developing lung. In this study, we characterized the spatial location, mRNA expression and Immunophenotyping of PDGFRα+ fibroblasts during sacculation and alveolarization. Confocal microscopy identified spatial association of PDGFRα expressing fibroblasts with proximal epithelial cells of the branching bronchioles and the dilating acinar tubules at E16.5; with distal terminal saccules at E18.5; and with alveolar epithelial cells at PN7 and PN28. Immunohistochemistry for alpha smooth muscle actin revealed that PDGFRα+ fibroblasts contribute to proximal peribronchiolar smooth muscle at E16.5 and to transient distal alveolar myofibroblasts at PN7. Time series RNA-Seq analyses of PDGFRα+ fibroblasts identified differentially expressed genes that, based on gene expression similarity were clustered into 7 major gene expression profile patterns. The presence of myofibroblast and smooth muscle precursors at E16.5 and PN7 was reflected by a two-peak gene expression profile on these days and gene ontology enrichment in muscle contraction. Additional molecular and functional differences between peribronchiolar smooth muscle cells at E16.5 and transient intraseptal myofibroblasts at PN7 were suggested by a single peak in gene expression at PN7 with functional enrichment in cell projection and muscle cell differentiation. Immunophenotyping of subsets of PDGFRα+ fibroblasts by flow cytometry confirmed the predicted increase in proliferation at E16.5 and PN7, and identified subsets of CD29+ myofibroblasts and CD34+ lipofibroblasts. These data can be further mined to develop novel hypotheses and valuable understanding of the molecular and cellular basis of alveolarization.
Asunto(s)
Fibroblastos/citología , Fibroblastos/metabolismo , Pulmón/embriología , Pulmón/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Animales , Antígenos CD/metabolismo , Bronquios/citología , Diferenciación Celular/genética , Embrión de Mamíferos/citología , Epitelio/metabolismo , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Proteínas Fluorescentes Verdes/metabolismo , Inmunofenotipificación , Pulmón/citología , Ratones Transgénicos , Miocitos del Músculo Liso/metabolismo , Miofibroblastos/citología , Fenotipo , Regiones Promotoras Genéticas/genética , Alveolos Pulmonares/citología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Factores de Tiempo , Factores de Transcripción/metabolismoRESUMEN
Septation of the gas-exchange saccules of the morphologically immature mouse lung requires regulated timing, spatial direction, and dosage of transforming growth factor (TGF)-ß signaling. We found that neonatal hyperoxia acutely initially diminished saccular TGF-ß signaling coincident with alveolar simplification. However, sustained hyperoxia resulted in a biphasic response and subsequent up-regulation of TGF-ß signaling, ultimately resulting in bronchopulmonary dysplasia. Significantly, we found that the TGF-ß-induced matricellular protein (TGFBI) was similarly biphasically altered in response to hyperoxia. Moreover, genetic ablation revealed that TGFBI was required for normal alveolar structure and function. Although the phenotype was not neonatal lethal, Tgfbi-deficient lungs were morphologically abnormal. Mutant septal tips were stunted, lacked elastin-positive tips, exhibited reduced proliferation, and contained abnormally persistent alveolar α-smooth muscle actin myofibroblasts. In addition, Tgfbi-deficient lungs misexpressed TGF-ß-responsive follistatin and serpine 1, and transiently suppressed myofibroblast platelet-derived growth factor α differentiation marker. Finally, despite normal lung volume, Tgfbi-null lungs displayed diminished elastic recoil and gas exchange efficiency. Combined, these data demonstrate that initial suppression of the TGF-ß signaling apparatus, as well as loss of key TGF-ß effectors (like TGFBI), underlies early alveolar structural defects, as well as long-lasting functional deficits routinely observed in chronic lung disease of infancy patients. These studies underline the complex (and often contradictory) role of TGF-ß and indicate a need to design studies to associate alterations with initial appearance of phenotypical changes suggestive of bronchopulmonary dysplasia.
Asunto(s)
Displasia Broncopulmonar/etiología , Displasia Broncopulmonar/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Hiperoxia/metabolismo , Pulmón/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Animales , Animales Recién Nacidos , Ratones , Miofibroblastos/metabolismo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal/fisiología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Bronchopulmonary dysplasia is a chronic lung disease of extreme preterm infants and results in impaired gas exchange. Although bronchopulmonary dysplasia is characterized histologically by alveolar-capillary simplification in animal models, it is clinically defined by impaired gas diffusion. With the use of a developmentally relevant model, we correlated alveolar-capillary structural simplification with reduced functional gas exchange as measured by the diffusing factor for carbon monoxide (DFCO). Neonatal mouse pups were exposed to >90% hyperoxia or room air during postnatal days 0 to 7, and then all pups were returned to room air from days 7 to 56. At day 56, DFCO was measured as the ratio of carbon monoxide uptake to neon dilution, and lungs were fixed for histologic assessment of alveolar-capillary development. Neonatal hyperoxia exposure inhibited alveolar-capillary septal development as evidenced by significantly increased mean linear intercept, increased airspace-to-septal ratio, decreased nodal density, and decreased pulmonary microvasculature. Importantly, alveolar-capillary structural deficits in hyperoxia-exposed pups were accompanied by a significant 28% decrease in DFCO (0.555 versus 0.400; P < 0.0001). In addition, DFCO was highly and significantly correlated with structural measures of reduced alveolar-capillary growth. Simplification of alveolar-capillary structure is highly correlated with impaired gas exchange function. Current mechanistic and therapeutic animal models of inhibited alveolar development may benefit from application of DFCO as an alternative physiologic indicator of alveolar-capillary development.
Asunto(s)
Capilares/patología , Capilares/fisiopatología , Alveolos Pulmonares/irrigación sanguínea , Alveolos Pulmonares/fisiopatología , Animales , Animales Recién Nacidos , Monóxido de Carbono/metabolismo , Difusión , Hiperoxia/patología , Hiperoxia/fisiopatología , Membranas , Ratones Endogámicos C57BL , Alveolos Pulmonares/patologíaRESUMEN
The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0-4 or 0-10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults.
Asunto(s)
Hiperoxia/fisiopatología , Lesión Pulmonar/fisiopatología , Animales , Animales Recién Nacidos , Hipoxia de la Célula , Femenino , Hiperoxia/complicaciones , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/metabolismo , Lesión Pulmonar/etiología , Masculino , Ratas Sprague-Dawley , Remodelación VentricularRESUMEN
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of extreme prematurity and is defined clinically by dependence on supplemental oxygen due to impaired gas exchange. Optimal gas exchange is dependent on the development of a sufficient surface area for diffusion. In the mammalian lung, rapid acquisition of distal lung surface area is accomplished in neonatal and early adult life by means of vascularization and secondary septation of distal lung airspaces. Extreme preterm birth interrupts secondary septation and pulmonary capillary development and ultimately reduces the efficiency of the alveolar-capillary membrane. Although pulmonary health in BPD infants rapidly improves over the first few years, persistent alveolar-capillary membrane dysfunction continues into adolescence and adulthood. Preventative therapies have been largely ineffective, and therapies aimed at promoting normal development of the air-blood barrier in infants with established BPD remain largely unexplored. The purpose of this review will be: (1) to summarize the histological evidence of aberrant alveolar-capillary membrane development associated with extreme preterm birth and BPD, (2) to review the clinical evidence assessing the long-term impact of BPD on alveolar-capillary membrane function, and (3) to discuss the need to develop and incorporate direct measurements of functional gas exchange into clinically relevant animal models of inhibited alveolar development.
Asunto(s)
Displasia Broncopulmonar , Capilares , Alveolos Pulmonares , Adolescente , Animales , Displasia Broncopulmonar/fisiopatología , Capilares/patología , Capilares/fisiopatología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Alveolos Pulmonares/irrigación sanguínea , Alveolos Pulmonares/patología , Alveolos Pulmonares/fisiopatologíaRESUMEN
BACKGROUND: Extreme preterm birth exposes the saccular lung to multiple teratogens, which ultimately retard alveolar development. Specifically, therapeutic high level oxygen supplementation adversely affects the premature lungs and results in blunted alveolarization. Prolonged hyperoxic lung injury has previously been shown to upregulate the matricellular protein Periostin (Postn) and stimulate ectopic accumulation of alpha smooth muscle actin (αSMA) myofibroblasts. Therapies that promote lung septation are lacking largely due to a lack of reliable early biomarkers of injury. Thus, we determined if Postn expression correlated with the initial appearance of myofibroblasts in the saccular lung and was required for early alveolar development. METHODS: Lung development in C57BL/6J mice following room-air (RA, 21%-O2) or continuous hyperoxia (85%-O2) from birth (P0) through postnatal day P14 was correlated with Postn and αSMA expression. Alveolarization in Postn knockout mice exposed to room-air, 60%-, and 85%-O2 was also examined. RESULTS: Postn was widely expressed in distal lung septa through P2 to P4 and peak expression coincided with accumulation of saccular myofibroblasts. Initially, 85%-O2 prematurely downregulated Postn and αSMA expression and suppressed proliferation before the first evidence of distal lung simplification at P4. By P14, chronic 85%-O2 resulted in secondary upregulation of Postn and αSMA in blunted septa. Myofibroblast differentiation and alveolar development was unaffected in Postn null mice and acute 85%-O2 exposure equally inhibited septal formation in Postn null and wild-type littermates. CONCLUSION: Postn expression is tightly correlated with the presence of αSMA-myofibroblasts and is a novel early biomarker of acutely inhibited alveolar septation during a crucial window of lung development.
Asunto(s)
Biomarcadores/metabolismo , Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/metabolismo , Moléculas de Adhesión Celular/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Terapia por Inhalación de Oxígeno/efectos adversos , Alveolos Pulmonares/metabolismo , Actinas/metabolismo , Animales , Animales Recién Nacidos , Western Blotting , Pesos y Medidas Corporales , Displasia Broncopulmonar/etiología , Moléculas de Adhesión Celular/genética , Inmunohistoquímica , Hibridación in Situ , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Miofibroblastos/metabolismo , Alveolos Pulmonares/crecimiento & desarrolloRESUMEN
Periostin is a 90-kDa member of the fasciclin-containing family and functions as part of the extracellular matrix. Periostin is expressed in a variety of tissues and expression is increased in airway epithelial cells from asthmatic patients. Recent studies have implicated a role for periostin in allergic eosinophilic esophagitis. To further define a role for periostin in Th2-mediated inflammatory diseases such as asthma, we studied the development of allergic pulmonary inflammation in periostin-deficient mice. Sensitization and challenge of periostin-deficient mice with OVA resulted in increased peripheral Th2 responses compared with control mice. In the lungs, periostin deficiency resulted in increased airway resistance and significantly enhanced mucus production by goblet cells concomitant with increased expression of Gob5 and Muc5ac compared with wild type littermates. Periostin also inhibited the expression of Gob5, a putative calcium-activated chloride channel involved in the regulation of mucus production, in primary murine airway epithelial cells. Our studies suggest that periostin may be part of a negative-feedback loop regulating allergic inflammation that could be therapeutic in the treatment of atopic disease.
Asunto(s)
Moléculas de Adhesión Celular/inmunología , Células Caliciformes/inmunología , Hipersensibilidad/inmunología , Neumonía/inmunología , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Western Blotting , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Células Caliciformes/metabolismo , Células Caliciformes/patología , Humanos , Hipersensibilidad/genética , Hipersensibilidad/metabolismo , Inmunohistoquímica , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Masculino , Metaplasia , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Moco/inmunología , Moco/metabolismo , Neumonía/genética , Neumonía/metabolismo , Bazo/citología , Bazo/inmunología , Bazo/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Neonates who are born preterm frequently have inadequate lung development to support independent breathing and will need respiratory support. The underdeveloped lung is also particularly susceptible to lung injury, especially during the first weeks of life. Consequently, respiratory support strategies in the early stages of premature lung disease focus on minimizing alveolar damage. As infants grow and lung disease progresses, it becomes necessary to shift respiratory support to a strategy targeting the often severe pulmonary heterogeneity and obstructive respiratory physiology. With appropriate management, time, and growth, even those children with the most extreme prematurity and severe lung disease can be expected to wean from respiratory support.
Asunto(s)
Displasia Broncopulmonar/metabolismo , Diferenciación Celular , Fibrosis Pulmonar Idiopática/metabolismo , Miofibroblastos/metabolismo , Alveolos Pulmonares/metabolismo , Enfisema Pulmonar/metabolismo , Animales , Displasia Broncopulmonar/patología , Humanos , Fibrosis Pulmonar Idiopática/patología , Miofibroblastos/patología , Alveolos Pulmonares/patología , Enfisema Pulmonar/patologíaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal form of interstitial lung disease (ILD). The precise molecular mechanisms of IPF remain poorly understood. However, analyses of mice receiving bleomycin (BLM) as a model of IPF established the importance of preceding inflammation for the formation of fibrosis. Periostin is a recently characterized matricellular protein involved in modulating cell functions. We recently found that periostin is highly expressed in the lung tissue of patients with IPF, suggesting that it may play a role in the process of pulmonary fibrosis. To explore this possibility, we administered BLM to periostin-deficient mice, and they subsequently showed a reduction of pulmonary fibrosis. We next determined whether this result was caused by a decrease in the preceding recruitment of neutrophils and macrophages in the lungs because of the lower production of chemokines and proinflammatory cytokines. We performed an in vitro analysis of chemokine production in lung fibroblasts, which indicated that periostin-deficient fibroblasts produced few or no chemokines in response to TNF-α compared with control samples, at least partly explaining the lack of inflammatory response and, therefore, fibrosis after BLM administration to periostin-deficient mice. In addition, we confirmed that periostin is highly expressed in the lung tissue of chemotherapeutic-agent-induced ILD as well as of patients with IPF. Taking these results together, we conclude that periostin plays a unique role as an inducer of chemokines to recruit neutrophils and macrophages important in the process of pulmonary fibrosis in BLM-administered model mice. Our results suggest a therapeutic potential for periostin in IPF and drug-induced ILD.
Asunto(s)
Moléculas de Adhesión Celular/fisiología , Quimiocinas/biosíntesis , Fibrosis Pulmonar/metabolismo , Anciano , Animales , Bleomicina/farmacología , Líquido del Lavado Bronquioalveolar , Moléculas de Adhesión Celular/genética , Células Cultivadas , Femenino , Humanos , Masculino , Ratones , Microscopía Confocal , Persona de Mediana Edad , Fibrosis Pulmonar/inducido químicamente , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Bronchopulmonary dysplasia (BPD) is a chronic lung disease in infants born extremely preterm, typically before 28 weeks' gestation, characterized by a prolonged need for supplemental oxygen or positive pressure ventilation beyond 36 weeks postmenstrual age. The limited number of autopsy samples available from infants with BPD in the postsurfactant era has revealed a reduced capacity for gas exchange resulting from simplification of the distal lung structure with fewer, larger alveoli because of a failure of normal lung alveolar septation and pulmonary microvascular development. The mechanisms responsible for alveolar simplification in BPD have not been fully elucidated, but mounting evidence suggests that aberrations in the cross-talk between growth factors of the lung mesenchyme and distal airspace epithelium have a key role. Animal models that recapitulate the human condition have expanded our knowledge of the pathology of BPD and have identified candidate matrix components and growth factors in the developing lung that are disrupted by conditions that predispose infants to BPD and interfere with normal vascular and alveolar morphogenesis. This review focuses on the deviations from normal lung development that define the pathophysiology of BPD and summarizes the various candidate mesenchyme-associated proteins and growth factors that have been identified as being disrupted in animal models of BPD. Finally, future areas of research to identify novel targets affected in arrested lung development and recovery are discussed.
Asunto(s)
Displasia Broncopulmonar/fisiopatología , Enfermedades del Prematuro/fisiopatología , Mesodermo/embriología , Mesodermo/fisiopatología , Proteínas/metabolismo , Transducción de Señal , Animales , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patología , Humanos , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/metabolismo , Enfermedades del Prematuro/patología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Pulmón/embriología , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Mesodermo/metabolismo , Mesodermo/patología , RatonesRESUMEN
RATIONALE: Clinical management of neonatal bronchopulmonary dysplasia (BPD) is often imprecise and can vary widely between different institutions and providers, due to limited objective measurements of disease pathology severity. There is critical need to improve guidance on the application and timing of interventional treatments, such as tracheostomy. OBJECTIVES: To generate an imaging-based clinical tool for early identification of those patients with BPD who are likely to require later tracheostomy and long-term mechanical ventilation. METHODS: We conducted a prospective cohort study of n = 61 infants (55 BPD, 6 preterm non-BPD). Magnetic resonance imaging (MRI) scores of lung parenchymal disease were used to create a binomial logistic regression model for predicting tracheostomy requirement. This model was further investigated using clinical variables and MRI-quantified tracheomalacia (TM). MEASUREMENTS AND MAIN RESULTS: A model for predicting tracheostomy requirement was created using MRI parenchymal score. This model had 89% accuracy, 100% positive predictive value (PPV), and 85% negative predictive value (NPV), compared with 84%, 60%, and 83%, respectively, when using only relevant clinical variables. In a subset of patients with airway MRI (n = 36), a model including lung and TM measurements had 83% accuracy, 92% PPV, and 78% NPV. CONCLUSIONS: MRI-based measurements of parenchymal disease and TM can be used to predict need for tracheostomy in infants with BPD, more accurately than clinical factors alone. This prediction model has strong potential as a clinical tool for physicians and families for early determination of tracheostomy requirement.
Asunto(s)
Displasia Broncopulmonar , Traqueomalacia , Displasia Broncopulmonar/diagnóstico por imagen , Displasia Broncopulmonar/terapia , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Pulmón/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Estudios Prospectivos , TraqueostomíaRESUMEN
Infants born prematurely worldwide have up to a 50% chance of developing bronchopulmonary dysplasia (BPD), a clinical morbidity characterized by dysregulated lung alveolarization and microvascular development. It is known that PDGFR alpha-positive (PDGFRA+) fibroblasts are critical for alveolarization and that PDGFRA+ fibroblasts are reduced in BPD. A better understanding of fibroblast heterogeneity and functional activation status during pathogenesis is required to develop mesenchymal population-targeted therapies for BPD. In this study, we utilized a neonatal hyperoxia mouse model (90% O2 postnatal days 0-7, PN0-PN7) and performed studies on sorted PDGFRA+ cells during injury and room air recovery. After hyperoxia injury, PDGFRA+ matrix and myofibroblasts decreased and PDGFRA+ lipofibroblasts increased by transcriptional signature and population size. PDGFRA+ matrix and myofibroblasts recovered during repair (PN10). After 7 days of in vivo hyperoxia, PDGFRA+ sorted fibroblasts had reduced contractility in vitro, reflecting loss of myofibroblast commitment. Organoids made with PN7 PDGFRA+ fibroblasts from hyperoxia in mice exhibited reduced alveolar type 1 cell differentiation, suggesting reduced alveolar niche-supporting PDGFRA+ matrix fibroblast function. Pathway analysis predicted reduced WNT signaling in hyperoxia fibroblasts. In alveolar organoids from hyperoxia-exposed fibroblasts, WNT activation by CHIR increased the size and number of alveolar organoids and enhanced alveolar type 2 cell differentiation.
Asunto(s)
Displasia Broncopulmonar , Hiperoxia , Animales , Displasia Broncopulmonar/etiología , Fibroblastos/metabolismo , Humanos , Hiperoxia/complicaciones , Recién Nacido , Pulmón/patología , Ratones , Miofibroblastos/metabolismoRESUMEN
OBJECTIVE: To characterize the safety of sildenafil in premature infants. STUDY DESIGN: A phase I, open-label trial of sildenafil in premature infants receiving sildenafil per usual clinical care (cohort 1) or receiving a single IV dose of sildenafil (cohort 2). Safety was evaluated based on adverse events (AEs), transaminase levels, and mean arterial pressure monitoring. RESULTS: Twenty-four infants in cohort 1 (n = 25) received enteral sildenafil. In cohort 2, infants received a single IV sildenafil dose of 0.25 mg/kg (n = 7) or 0.125 mg/kg (n = 2). In cohort 2, there was one serious AE related to study drug involving hypotension associated with a faster infusion rate than specified by the protocol. There were no AEs related to elevated transaminases. CONCLUSION: Sildenafil was well tolerated by the study population. Drug administration times and flush rates require careful attention to prevent infusion-related hypotension associated with faster infusions of IV sildenafil in premature infants. CLINICAL TRIAL: ClinicalTrials.gov Identifier: NCT01670136.
Asunto(s)
Hipotensión , Enfermedades del Prematuro , Humanos , Hipotensión/inducido químicamente , Hipotensión/tratamiento farmacológico , Recien Nacido Extremadamente Prematuro , Recién Nacido de Bajo Peso , Recién Nacido , Enfermedades del Prematuro/tratamiento farmacológico , Citrato de Sildenafil/efectos adversosRESUMEN
OBJECTIVE: The decision for tracheostomy for bronchopulmonary dysplasia (BPD) is highly variable and often dictated by local practice. We aimed to characterize morbidity, mortality, and respiratory outcomes in preterm infants undergoing tracheostomy for severe BPD. STUDY DESIGN: We retrospectively reviewed a single-center 4-year cohort of all infants born <33 weeks gestational age (GA) that required tracheostomy due to severe BPD. Indications for tracheostomy apart from BPD were excluded. Demographic information, comorbidities, respiratory management, age at tracheostomy, post-discharge respiratory outcomes, and survival were examined up to at least 5 years of age. RESULTS: At a mean corrected GA of 43.3 weeks, 49 preterm infants with severe BPD required tracheostomy. Forty-six infants (94%) had long-term follow-up. Compared to survivors, the 12 (26.1%) infants that died were significantly more likely to be small for gestational age (SGA) or require treatment for pulmonary hypertension. GA, birth weight, sex, antenatal corticosteroid exposure, need for patent ductus arteriosus ligation, and magnitude of respiratory support at tracheostomy placement were not associated with mortality. At the latest follow-up, 97% were liberated from mechanical ventilation and 79% decannulated. Morbidities of the upper airway were common, and 13/27 (47%) decannulated infants had required airway reconstruction. CONCLUSION: Preterm infants undergoing tracheostomy experienced significant mortality, particularly those who were SGA or had pulmonary hypertension. However, by 5 years of age, most infants liberalized from mechanical ventilation and decannulated. Magnitude of respiratory support at time of tracheostomy was not associated with mortality and should not deter intervention. Nearly half of patients required airway reconstruction before decannulation.