Gene expression analysis after prenatal tracheal ligation in fetal rat as a model of stimulated lung growth

Burgos, Carmen Mesas; Nord, Magnus; Didon, Lukas; Eklöf, Ann-Christine; Frenckner, Björn

doi:10.1016/j.jpedsurg.2008.06.020

Cited by 20 publications

(21 citation statements)

References 39 publications

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“…Nevertheless, we were unable to study surfactant status after FETO because of administration of prenatal steroids. Coinciding with alveolization, experimental TO modified extracellular matrix homeostasis (see literature overview in Table 4), as denoted by increased elastogenesis (6,30,62), myogenic markers (51), and reshaping molecules like tissue inhibitor of matrix metalloproteinase-1 (62) and connective tissue growth factor (39,53). However, despite improved lung morphology and growth, interstitial changes might be inappropriate for immediate neonatal lung mechanics, as denoted by low hysteresivity in the present study, altered lung compliance after reversible TO in CDH sheep despite normal surfactant status (17), and negligible improvement of neonatal respiratory function after FETO (31).…”

Section: Discussionmentioning

confidence: 99%

“…No evidence so far Decrease in healthy rat (39) No evidence so far Type II cells Decrease in healthy and CDH rabbit (18,66) No evidence so far TTF-1 Decrease in CDH rat (9) No evidence so far Extracellular matrix ␣-SMA Increase in healthy mouse (51) No evidence so far Collagens Increase in healthy sheep and mouse (40,53) No evidence so far Tropoelastin Increase in CDH sheep and rabbit (6,62) No evidence so far Increase in healthy sheep and mouse (30,53) No evidence so far Fibronectin Increase in healthy rat and sheep (39,53) No evidence so far MMPs Increase in MMP-2 and Ϫ9 in CDH sheep (20) No evidence so far TIMPs Increase in TIMP-1 in CDH rabbit (62) No evidence so far CTGF Increase in healthy rat and sheep (39,53) No evidence so far ␣-SMA, smooth muscle actin; CDH, congenital diaphragmatic hernia; CTGF, connective tissue growth factor; FETO, temporary fetoscopic endoluminal tracheal occlusion; MMP, matrix metalloproteinase; ROCK, Rho-associated kinase; TGF-␤, transforming growth factor-␤; TIMP, tissue inhibitor of matrix metalloproteinase; TO, tracheal occlusion; TTF-1, transcription thyroid factor-1.…”

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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%

mentioning

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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“…CTGF plays an important role in promoting alveolarisation and microvascular development in the later stages of foetal lung development [12] . It is theoretically possible therefore that a decrease in lung fluid may be associated with reduced production of these growth factors.…”

Section: Possible Mechanisms Of Abnormal Lung Growthmentioning

confidence: 99%

Pulmonary Effects of Prolonged Oligohydramnios following Mid-Trimester Rupture of the Membranes – Antenatal and Postnatal Management

Williams¹,

Hutchings

Hubinont

et al. 2011

Neonatology

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Mid-trimester, preterm prelabour rupture of the membranes (PPROM) with prolonged oligohydramnios remains a challenge for both obstetricians and neonatologists. Although survival rates have improved, morbidity remains common particularly due to pulmonary insufficiency and pulmonary hypertension. The aetiology of abnormal lung development is unknown but may depend critically on pulmonary vascular development. Antenatal evaluation of at-risk foetuses by three-dimensional ultrasound and MRI is possible but the techniques need to be further assessed. Antenatal corticosteroids given in cases of PPROM reduce the incidence of neonatal death, respiratory distress syndrome, intraventricular haemorrhage and necrotising enterocolitis without increasing maternal or neonatal infection. The true risk-benefit ratio of antibiotics, tocolysis and strategies to normalise amniotic fluid volume remains less clear. There is no consensus regarding the optimal ventilation strategy to support infants with pulmonary insufficiency following PPROM, and further work is required to determine whether and which pulmonary vasodilators improve long-term outcome in these infants.

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“…Another investigation evidenced reduced air space, thicker interstitial mesenchymal compartments, and presence of embedded capillaries in the prenatal lung consequently to Fgf18 gene targeting in mice, which indicates involvement at saccular stage as well (45). Consistently, FGF18 expression was found to be enhanced in the stimulation of fetal rat lung growth induced by tracheal ligation (34).…”

mentioning

confidence: 69%

Profiling target genes of FGF18 in the postnatal mouse lung: possible relevance for alveolar development

Franco-Montoya

Boucherat

Thibault

et al. 2011

Physiological Genomics

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Better understanding alveolarization mechanisms could help improve prevention and treatment of diseases characterized by reduced alveolar number. Although signaling through fibroblast growth factor (FGF) receptors is essential for alveolarization, involved ligands are unidentified. FGF18, the expression of which peaks coincidentally with alveolar septation, is likely to be involved. Herein, a mouse model with inducible, lung-targeted FGF18 transgene was used to advance the onset of FGF18 expression peak, and genome-wide expression changes were determined by comparison with littermate controls. Quantitative RT-PCR was used to confirm expression changes of selected up- and downregulated genes and to determine their expression profiles in the course of lung postnatal development. This allowed identifying so-far unknown target genes of the factor, among which a number are known to be involved in alveolarization. The major target was adrenomedullin, a promoter of lung angiogenesis and alveolar development, whose transcript was increased 6.9-fold. Other genes involved in angiogenesis presented marked expression increases, including Wnt2 and cullin2. Although it appeared to favor cell migration notably through enhanced expression of Snai1/2, FGF18 also induced various changes consistent with prevention of epithelial-mesenchymal transition. Together with antifibrotic effects driven by induction of E prostanoid receptor 2 and repression of numerous myofibroblast markers, this could prevent alveolar septation-driving mechanisms from becoming excessive and deleterious. Last, FGF18 up- or downregulated genes of extracellular matrix components and epithelial cell markers previously shown to be up- or downregulated during alveolarization. These findings therefore argue for an involvement of FGF18 in the control of various developmental events during the alveolar stage.

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Gene expression analysis after prenatal tracheal ligation in fetal rat as a model of stimulated lung growth

Cited by 20 publications

References 39 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 Effects of Prolonged Oligohydramnios following Mid-Trimester Rupture of the Membranes – Antenatal and Postnatal Management

Profiling target genes of FGF18 in the postnatal mouse lung: possible relevance for alveolar development

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