Assessment of the nitrofen model of congenital diaphragmatic hernia and of the dysregulated factors involved in pulmonary hypoplasia

Montalva, Louise; Zani, Augusto

doi:10.1007/s00383-018-4375-5

Cited by 37 publications

(47 citation statements)

References 172 publications

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“…7 The nitrofen model relies on the administration of a herbicide (2,4dichlorophenyl-p-nitrophenyl ether) to a pregnant rat at 9 days of gestation (E9), which causes pulmonary hypoplasia in 100% of the offspring and a diaphragmatic defect in 50-60% of the litter. 8 In the nitrofen model, fetuses with CDH have decreased distal vessel density, increased muscularization of small arteries, resulting in increased pulmonary vascular wall thickness. 7,9 In fact, both medial and adventitial layers of the vascular walls are thickened in the experimental and human CDH.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

2019

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Congenital diaphragmatic hernia (CDH) is a severe birth defect that is characterized by pulmonary hypoplasia and pulmonary hypertension (PHTN). PHTN secondary to CDH is a result of vascular remodeling, a structural alteration in the pulmonary vessel wall that occurs in the fetus. Factors involved in vascular remodeling have been reported in several studies, but their interactions remain unclear. To help understand PHTN pathophysiology and design novel preventative and treatment strategies, we have conducted a systematic review of the literature and comprehensively analyzed all factors and pathways involved in the pathogenesis of pulmonary vascular remodeling secondary to CDH in the nitrofen model. Moreover, we have linked the dysregulated factors with pathways involved in human CDH. Of the 358 full-text articles screened, 75 studies reported factors that play a critical role in vascular remodeling secondary to CDH. Overall, the impairment of epithelial homeostasis present in pulmonary hypoplasia results in altered signaling to endothelial cells, leading to endothelial dysfunction. This causes an impairment of the crosstalk between endothelial cells and pulmonary artery smooth muscle cells, resulting in increased smooth muscle cell proliferation, resistance to apoptosis, and vasoconstriction, which clinically translate into PHTN.

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Section: Introductionmentioning

confidence: 99%

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

2019

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“…1E to L, fig. S3A and B) (32,37,38). AFSC-EV administration rescued cell proliferation back to control levels and improved epithelial cell differentiation, as evidenced by a reduction of SOX9+ progenitor cell density (Fig 1E to F) and by an increased expression of SPC ( Fig.…”

Section: Hypoplastic Lungs Have Decreased Cell Proliferation and Delamentioning

confidence: 86%

“…The most robust experimental model of pulmonary hypoplasia relies on nitrofen administration to pregnant rats at embryonic day (E) 9.5 (30,31), which mainly targets retinoic acid synthesis (32). In this model, the whole litter has an impairment in lung development that is analogous to that of human fetuses (2,(30)(31)(32)(33). In utero nitrofen exposure causes a reduction in bronchiolar divisions and in the number of airspaces compared to lungs from unexposed fetuses (Fig.…”

Section: Afsc-ev Administration Promotes Growth and Maturation In Fetmentioning

confidence: 99%

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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“…[14][15][16] This model has shown to be valuable because it replicates pulmonary underdevelopment with a similar phenotype to that of human CDH, and with an alteration of factors and pathways that are relevant for normal human lung development. 17 To survive, human babies with CDH require immediate intubation, mechanical intervention, and intensive care management. 18 Likewise, pups exposed to even a small dose of nitrofen have such severe neonatal respiratory distress at birth that they would require intubation and mechanical intervention to survive.…”

Section: Nitrofen Modelmentioning

confidence: 99%

“…21 Moreover, a recent systematic review on studies that employed nitrofen to model CDH in rats has shown that the herbicide induces CDH in 52% of rat fetuses and PH in 100% of them when administered at embryonic day (E) 9 to pregnant dams. 17 Similarly, nitrofen administration to pregnant mice at E12 induces PH prior to the development of a diaphragmatic defect, with a reduction in surfactant proteins and markers of differentiated epithelial cells when compared with age-matched controls. 16 The nitrofen model has also been used to study the pathogenesis of pulmonary vascular remodeling secondary to CDH and to test potential interventions for PHTN.…”

Section: Nitrofen Modelmentioning

confidence: 99%

Congenital Diaphragmatic Hernia: State of the Art in Translating Experimental Research to the Bedside

et al. 2019

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Congenital diaphragmatic hernia (CDH) is a devastating disease that still carries a high mortality and morbidity rate. Poor outcomes for fetuses and infants with CDH are mainly related to pulmonary hypoplasia (PH) and pulmonary vascular remodeling that leads to pulmonary hypertension (PHTN). Over the last five decades, research efforts have focused on modeling CDH not only to study the pathophysiology of the diaphragmatic defect, pulmonary hypoplasia, and pulmonary hypertension, but also to identify therapies that would promote lung growth and maturation, and correct vascular remodeling. As CDH is a multifactorial condition whose etiology remains unknown, there is not a single model of CDH, rather several ones that replicate different aspects of this disease. While small animals like the mouse and the rat have mainly been used to uncover biological pathways underlying the diaphragmatic defect and poor lung growth, larger animals like the lamb and the rabbit models have been instrumental for pursuing medical and surgical interventions. Overall, the use of animal models has indeed advanced our knowledge on CDH and helped us test innovative therapeutic options. For example, the lamb model of CDH has been the paradigm for testing fetal surgical procedures, including tracheal occlusion, which has been translated to clinical use. In this review, we outline the induction protocols of CDH in animals with the use of chemicals, dietary changes, genetic alterations, and surgical maneuvers, and we describe the studies that have translated experimental results to the bedside.

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Assessment of the nitrofen model of congenital diaphragmatic hernia and of the dysregulated factors involved in pulmonary hypoplasia

Cited by 37 publications

References 172 publications

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

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

Congenital Diaphragmatic Hernia: State of the Art in Translating Experimental Research to the Bedside

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