Unique Tracheal Fluid MicroRNA Signature Predicts Response to FETO in Patients With Congenital Diaphragmatic Hernia

Pereira-Terra, Patrícia; Deprest, Jan; Kholdebarin, Ramin; Khoshgoo, Naghmeh; DeKoninck, Philip; Munck, Anne A Boerema-De; Wang, Jinxia; Zhu, Fuqin; Rottier, Robbert J.; Correia‐Pinto, Jorge; Tibboel, Dick; Post, Martin; Keijzer, Richard

doi:10.1097/sla.0000000000001054

Cited by 59 publications

(85 citation statements)

References 55 publications

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“…immunoreactivity was recently reported during alveolar formation in three CDH newborns (45). However, the intensity of chromogen staining does not necessarily correlate linearly with antigen concentration (55).…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, both signalings contribute to accelerate alveolization owing to rapid upregulation of genes encoding myogenic factors, tropoelastin, and collagens. Recently, higher expression levels of microRNA-200 family members in the tracheal fluid of human CDH fetuses undergoing FETO were interpreted as part of a negative-feedback loop on microRNA-200 expression due to stretch-induced increase in TGF-␤ expression (45). Consistent with this assumption and the inhibition of Smad2/3 activity in vitro by microRNA-200b (45), the present study demonstrates elevated TGF-␤ transcripts and decreased p-Smad2/3 levels in FETO lungs.…”

Section: Discussionmentioning

confidence: 99%

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Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?

Vuckovic

Herber-Jonat

Flemmer

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-β pathway, a key player in lung development and repair. Pulmonary expression of TGF-β signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant-phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-β/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-β transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and α-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-β/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?

Vuckovic

Herber-Jonat

Flemmer

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Finally, recent studies implicated microRNAs in the development of CDH, but it remains to be seen whether the changes observed in miR-200b and miR-10a are a cause or a consequence of CDH [41,42].…”

Section: Pulmonary Vascular Development In Congenital Diaphragmatic Hmentioning

confidence: 99%

Pulmonary vascular development in congenital diaphragmatic hernia

et al. 2018

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Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterised by a diaphragmatic defect, persistent pulmonary hypertension (PH) and lung hypoplasia. The relative contribution of these three elements can vary considerably in individual patients. Most affected children suffer primarily from the associated PH, for which the therapeutic modalities are limited and frequently not evidence based. The vascular defects associated with PH, which is characterised by increased muscularisation of arterioles and capillaries, start to develop early in gestation. Pulmonary vascular development is integrated with the development of the airway epithelium. Although our knowledge is still incomplete, the processes involved in the growth and expansion of the vasculature are beginning to be unravelled. It is clear that early disturbances of this process lead to major pulmonary growth abnormalities, resulting in serious clinical challenges and in many cases death in the newborn. Here we provide an overview of the current molecular pathways involved in pulmonary vascular development. Moreover, we describe the abnormalities associated with CDH and the potential therapeutic approaches for this severe abnormality. Normal pulmonary vascular developmentHuman lung development can be divided into different stages based on histology, starting with the embryonic stage at 4 weeks of gestation, followed by the pseudoglandular stage in which branching of the lung buds continues. During the canalicular stage, starting at ∼16 weeks of gestation, the terminal bronchioli are formed. From 24 weeks of gestation until term, the saccular stage, airspaces widen and alveoli are formed. During the alveolar stage, which persists into the postnatal period up to 3 years of age, maturation of the airways occurs [1]. Concomitant with the expansion of the airways is the adaptation of the microvasculature to optimise the exchange of oxygen and carbon dioxide between the blood and the airways. We and others have shown that very early in lung development pulmonary vessels are present and connected to the systemic circulation. The vasculature develops in close relation with the airways and is a rate-limiting factor in branching morphogenesis [2][3][4]. This implies that the pulmonary vasculature plays an important role in lung development. The formation of new blood vessels primarily occurs through

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“…Clinical studies have used miRNAs to treat hepatitis C virus and cancer, with multiple other targets under preclinical investigation . We discovered that human lungs in fetuses with CDH between 22 and 25 gestational weeks (canalicular stage) show significant upregulation of miR‐200b and miR‐10a. Also, tracheal fluid from human CDH fetuses undergoing fetal endoscopic tracheal occlusion (FETO) with a treatment response (measurable lung growth and survival) had higher levels of miR‐200 family members than nonresponders .…”

Section: Introductionmentioning

confidence: 99%

MicroRNA 200b is upregulated in the lungs of fetal rabbits with surgically induced diaphragmatic hernia

et al. 2018

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Unique Tracheal Fluid MicroRNA Signature Predicts Response to FETO in Patients With Congenital Diaphragmatic Hernia

Cited by 59 publications

References 55 publications

Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?

Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?

Pulmonary vascular development in congenital diaphragmatic hernia

MicroRNA 200b is upregulated in the lungs of fetal rabbits with surgically induced diaphragmatic hernia

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