Vascular and ventilatory mechanical responses in three different stages of pulmonary development in the rabbit model of congenital diaphragmatic hernia

Figueira, Rebeca Lopes; Costa, Karina Miura da; Marsico, Ana Laura; Milani, Thamires Melchiades da Silva; Gonçalves, Walusa Assad; Borges, Marcos C.; Silva, Orlando Castro e; Sbragia, Lourenço

doi:10.1590/s0102-865020180100000002

Cited by 4 publications

(7 citation statements)

References 21 publications

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“…To test the effects of rAFSC-EVs in vivo, we used a surgical model of pulmonary hypoplasia secondary to CDH in fetal rabbits, as it allowed us to topically deliver our treatment (Fig. 5A) (41). To prevent rAFSC-EV egression, we performed tracheal occlusion on rabbit fetuses (movie S6), a procedure currently used in clinical trials for selected CDH human fetuses (42).…”

Section: Toward Clinical Translation Of Afsc-evs As Treatment For Fet...mentioning

confidence: 99%

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Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents

et al. 2021

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Fetal lung underdevelopment, also known as pulmonary hypoplasia, is characterized by decreased lung growth and maturation. The most common birth defect found in babies with pulmonary hypoplasia is congenital diaphragmatic hernia (CDH). Despite research and clinical advances, babies with CDH still have high morbidity and mortality rates, which are directly related to the severity of lung underdevelopment. To date, there is no effective treatment that promotes fetal lung growth and maturation. Here, we describe a stem cell–based approach in rodents that enhances fetal lung development via the administration of extracellular vesicles (EVs) derived from amniotic fluid stem cells (AFSCs). Using fetal rodent models of pulmonary hypoplasia (primary epithelial cells, organoids, explants, and in vivo), we demonstrated that AFSC-EV administration promoted branching morphogenesis and alveolarization, rescued tissue homeostasis, and stimulated epithelial cell and fibroblast differentiation. We confirmed this regenerative ability in in vitro models of lung injury using human material, where human AFSC-EVs obtained following good manufacturing practices restored pulmonary epithelial homeostasis. Investigating EV mechanism of action, we found that AFSC-EV beneficial effects were exerted via the release of RNA cargo. MicroRNAs regulating the expression of genes involved in lung development, such as the miR17–92 cluster and its paralogs, were highly enriched in AFSC-EVs and were increased in AFSC-EV–treated primary lung epithelial cells compared to untreated cells. Our findings suggest that AFSC-EVs hold regenerative ability for underdeveloped fetal lungs, demonstrating potential for therapeutic application in patients with pulmonary hypoplasia.

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Section: Toward Clinical Translation Of Afsc-evs As Treatment For Fet...mentioning

confidence: 99%

“…In vivo-Pulmonary hypoplasia was induced by surgical creation of CDH at E25 in New Zealand rabbits (41). At E27, tracheal ligation was performed alone or after intratracheal administration of a 50-l bolus containing rAFSC-EVs, rMSC-EVs, or hAFSC-EVs (movie S6).…”

Section: Experimental Models Of Pulmonary Hypoplasiamentioning

confidence: 99%

Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents

et al. 2021

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“…Human studies on Rrs in CDH are scarce, and most reports are from animal experiments. Figueira et al reported that the Rrs levels of CDH model rabbits were higher than those of term infants and comparable to that in preterm infants 15 . They also demonstrated that Rrs levels did not vary significantly in the time series from birth 15 .…”

Section: Discussionmentioning

confidence: 87%

“…14 Rrs levels of CDH model rabbits were higher than those of term infants and comparable to that in preterm infants. 15 They also demonstrated that Rrs levels did not vary significantly in the time series from birth. 15 In humans, airway resistance in preterm infants after tracheal suction ranged between 137 and 352 cmH 2 O･kg/L/s.…”

Section: Discussionmentioning

confidence: 95%

“…15 They also demonstrated that Rrs levels did not vary significantly in the time series from birth. 15 In humans, airway resistance in preterm infants after tracheal suction ranged between 137 and 352 cmH 2 O･kg/L/s. 16 Di Fiore et al, reported that the mean Rrs level on inhaled nitric oxide in preterm infants was 231 ± 71 cmH 2 O･kg/L/s.…”

Section: Discussionmentioning

confidence: 95%

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Respiratory function testing for guiding ventilator mode conversion in congenital diaphragmatic hernia

Kimura,

Toyoshima,

Shimokaze

et al. 2024

Pediatric Pulmonology

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IntroductionFor patients with a congenital diaphragmatic hernia, conventional mechanical ventilation (CMV) and high‐frequency oscillatory ventilation (HFOV) are used in initial ventilatory management. HFOV has recently been recommended as a rescue therapy; however, we use HFOV for initial ventilation management, with a preoperative challenge test for CMV conversion and respiratory function testing at the time of CMV conversion. We aimed to compare patient characteristics between CMV conversion‐ and HFOV‐preferred treatment groups.MethodsVentilator settings and blood gases were retrospectively evaluated pre‐ and post‐CMV conversion, and respiratory function tests for compliance of the respiratory system (Crs) and for resistance of the respiratory system (Rrs) were performed during the trial to CMV conversion.ResultsNo differences were observed between the CMV conversion‐ and HFOV‐preferred groups regarding gestational age, birth weight, and observed/expected lung area‐to‐head circumference ratios. The median Crs (ml/cmH2O/kg) and Rrs (cmH2O･kg/L/s) in the CMV conversion‐ and HFOV‐preferred groups was 0.42 versus 0.53 (p = .44) and 467 versus 327 (p = .045), respectively. The pre and posttrial amount of change in blood gas levels and ventilator parameters in the CMV conversion‐ and HFOV‐preferred groups were as follows: mean airway pressure, −2.0 versus 0 cmH2O; partial pressure of carbon dioxide, 6.1 versus 2.9 Torr; alveolar‐arterial oxygen difference, −39.5 versus −50 Torr; and oxygenation index, −1.0 versus −0.6; respectively.ConclusionRespiratory function tests were useful in tailoring ventilator settings. Patients with high Rrs values responded better to CMV conversion.

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Impaired Fetal Lung Development can be Rescued by Administration of Extracellular Vesicles Derived from Amniotic Fluid Stem Cells

Antounians

Catania

Montalva

et al. 2020

Preprint

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Incomplete lung development, also known as pulmonary hypoplasia, is a recognized cause of neonatal death and poor outcome for survivors. To date, there is no effective treatment that promotes fetal lung growth and maturation. Herein, we describe a novel stem cell-based approach that enhances fetal lung development via the administration of extracellular vesicles (EVs) derived from amniotic fluid stem cells (AFSCs). In experimental models of pulmonary hypoplasia, administration of AFSC-EVs promoted lung branching morphogenesis and alveolarization, and stimulated pulmonary epithelial cell and fibroblast differentiation. This regenerative ability was confirmed in two models of injured human lung cells, where human AFSC-EVs obtained following good manufacturing practices restored pulmonary epithelial homeostasis. AFSC-EV beneficial effects were exerted via the release of RNA cargo, primarily miRNAs, that regulate the expression of genes involved in fetal lung development. Our findings suggest that AFSC-EVs hold regenerative ability for underdeveloped fetal lungs, demonstrating potential for therapeutic application.One Sentence SummaryFetal lung regeneration via administration of extracellular vesicles derived from amniotic fluid stem cells

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Vascular and ventilatory mechanical responses in three different stages of pulmonary development in the rabbit model of congenital diaphragmatic hernia

Cited by 4 publications

References 21 publications

Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents

Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents

Respiratory function testing for guiding ventilator mode conversion in congenital diaphragmatic hernia

Impaired Fetal Lung Development can be Rescued by Administration of Extracellular Vesicles Derived from Amniotic Fluid Stem Cells

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