Gene expression analysis in hypoplastic lungs in the nitrofen model of congenital diaphragmatic hernia

Burgos, Carmen Mesas; Uggla, Andreas Ringman; Fagerström‐Billai, Fredrik; Eklöf, Ann-Christine; Frenckner, Björn; Nord, Magnus

doi:10.1016/j.jpedsurg.2009.09.023

Cited by 23 publications

(16 citation statements)

References 56 publications

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“…qPCR is considered as the gold standard to study the transcriptome and allows the use of small amounts of starting material, which is advantageous with regard to hypoplastic tissue. Recently, microarray technology has established gene expression profile in the CDH rat model 21. Despite useful information provided about the expression of hundreds of genes, many issues are raised by this concept.…”

Section: Discussionmentioning

confidence: 99%

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Signaling molecules in the fetal rabbit model for congenital diaphragmatic hernia

Vuckovic

Roubliova

Votino

et al. 2012

Pediatric Pulmonology

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Summary. Rationale and objectives: Little is known about molecular changes in lungs of fetal rabbits with surgically induced diaphragmatic hernia (DH). Therefore, we examined in this model gene expressions of pivotal molecules for the developing lung. Methods: At day 23 of gestation, DH was created in 12 fetuses from 4 does. Both lungs from six live DH fetuses and from six unoperated controls were harvested and weighed at term. Transcription of 15 genes involved in alveolarization, angiogenesis, regulation of vascular tone, or epithelial maturation was investigated by real-time quantitative polymerase chain reaction. Main results: DH decreased lung-to-body weight ratio (P < 0.001). A bilateral downregulation was seen for genes encoding for tropoelastin (P < 0.01), lysyl oxidase (P < 0.05), fibulin 5 (P < 0.05), and cGMP specific phosphodiesterase 5 (P < 0.05). Lower mRNA levels for endothelial nitric oxide synthase occurred in the ipsilateral lung (P < 0.05). Conclusions: Experimental DH in fetal rabbits disrupted transcription of genes implicated in lung growth and function. Similarities with the human disease make this model appropriate for investigation of new prenatal therapies. Pediatr Pulmonol. ß

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Section: Discussionmentioning

confidence: 99%

“…Recently, microarray technology has established gene expression profile in the CDH rat model. 21 Despite useful information provided about the expression of hundreds of genes, many issues are raised by this concept. Instead of exploring the genome, we used qPCR to focus on specific target genes that may be relevant in the setting of CDH.…”

Section: Discussionmentioning

confidence: 99%

Signaling molecules in the fetal rabbit model for congenital diaphragmatic hernia

Vuckovic

Roubliova

Votino

et al. 2012

Pediatric Pulmonology

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“…The nitrofen model of CDH in rats is a valuable tool for studying molecular and cellular alterations in HH which are difficult in humans. Although a few groups have looked at changes in growth factors [19,35,36], and cardiac and ECM genes [19,37,38] in the nitrofen model of CDH, CDH+ cardiac cells have not been cultured or subjected to specific engineered environments to study their response to biophysical cues. The key novel findings of this study are: 1) cell proliferation and cardiomyocyte maturity were decreased in CDH+ hearts compared to healthyimportantly these effects were not caused by a direct effect of nitrofen on cardiomyocytes in the developing hearts; 2) in culture, CDH+ cardiomyocytes remained immature with increased proliferative potential compared to healthy cardiomyocytes; 3) ECM derived from CDH+ hearts significantly reduced both healthy and CDH+ cardiomyocyte proliferation compared healthy cardiac ECM; and 4) cyclic mechanical stretch promoted sarcomere maturation in CDH+ cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix and cyclic stretch alter fetal cardiomyocyte proliferation and maturation in a rodent model of heart hypoplasia

Watson

Williams

Wang

et al. 2020

Preprint

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Birth defects, particularly those that affect development of the heart, are a leading cause of morbidity and mortality in infants and young children. Babies born with heart hypoplasia (HH) disorders often have a poor prognosis. It remains unclear whether cardiomyocytes from hypoplastic hearts retain the potential to recover growth, although this knowledge would be beneficial for developing therapies for HH disorders. The objective of this study was to determine the proliferation and maturation potential of cardiomyocytes from hypoplastic hearts and whether these behaviors are influenced by biophysical signaling from the extracellular matrix (ECM) and cyclic mechanical stretch. Congenital diaphragmatic hernia (CDH)-associated HH was induced in rat fetuses by maternal exposure to nitrofen. Hearts were isolated from embryonic day 21 nitrofen-treated fetuses positive for CDH (CDH+) and from fetuses without nitrofen administration during gestation. CDH+ hearts were smaller and had decreased myocardial proliferation, along with evidence of decreased maturity compared to healthy hearts. In culture, CDH+ cardiomyocytes remained immature and demonstrated increased proliferative capacity compared to their healthy counterparts. Culture on ECM derived from CDH+ hearts led to a significant reduction in proliferation for both CDH+ and healthy cardiomyocytes. Healthy cardiomyocytes were dosed with exogenous nitrofen to examine whether nitrofen may have an abhorrent effect on the proliferative ability of cardiomyocyte, yet no significant change in proliferation was observed. When subjected to stretch, CDH+ cardiomyocytes underwent lengthening of sarcomeres while healthy cardiomyocyte sarcomeres were unaffected. Taken together, our results suggest that alterations to environmental cues such as ECM and stretch may be important factors in the pathological progression of HH.

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“…Current microarray technology allows global gene expression analysis that will identify genes and pathways and potential therapeutic targets in CDH. This has already been started in animal models for CDH, such as the nitrofen rat [54] or after TO in a rat model with normal lungs [55].…”

Section: Overcoming Limitations Of Fetal Interventionmentioning

confidence: 99%

Antenatal management of isolated congenital diaphragmatic hernia today and tomorrow: ongoing collaborative research and development

Deprest

Coppi

2012

Journal of Pediatric Surgery

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Gene expression analysis in hypoplastic lungs in the nitrofen model of congenital diaphragmatic hernia

Cited by 23 publications

References 56 publications

Signaling molecules in the fetal rabbit model for congenital diaphragmatic hernia

Signaling molecules in the fetal rabbit model for congenital diaphragmatic hernia

Extracellular matrix and cyclic stretch alter fetal cardiomyocyte proliferation and maturation in a rodent model of heart hypoplasia

Antenatal management of isolated congenital diaphragmatic hernia today and tomorrow: ongoing collaborative research and development

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