Abnormal platelet-derived growth factor signaling accounting for lung hypoplasia in experimental congenital diaphragmatic hernia

Dingemann, Jens; Doi, Takashi; Ruttenstock, Elke; Puri, Prem

doi:10.1016/j.jpedsurg.2010.06.014

Cited by 23 publications

(22 citation statements)

References 26 publications

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“…Our fetuses were examined on gestational day 21, where there was no difference in PDGFR-␣ protein levels between control and CDH animals. This is in agreement with Dingemann et al (9). On day 21 they report no difference in PDGFR-␣ and PDGF-A mRNA expression between the nitrofen-treated group and normal controls.…”

Section: Discussionsupporting

confidence: 93%

“…PDGF-A and PDGFR-␣ are known to play a crucial role in lung development (27), and Dingemann et al (9) have shown an increased expression of PDGF-A and PDGFR-␣ in the nitrofen model on gestational days 18 and 15, respectively. They suggest that an increased PDGF-A signaling causes increased oxidative stress, which leads to pulmonary hypoplasia.…”

Section: Discussionmentioning

confidence: 99%

“…There is also evidence of an involvement of PDGF-A in PH. Expression of PDGF-A is elevated in lung biopsies from patients with PH (17), and the ␣-receptor is elevated in the ovine model of PH mentioned above (4,9). However, reports on the role of PDGF-A in PH are contradictory.…”

mentioning

confidence: 99%

“…These differences were no longer detectable on day 21 (9). PDGF-A knockout leads to defective alveologenesis and is embryonically lethal (27).…”

mentioning

confidence: 99%

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Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia

Chang

Uggla²,

Österholm

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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The pathophysiology of congenital diaphragmatic hernia (CDH) is constituted by pulmonary hypoplasia and pulmonary hypertension (PH). We previously reported successful treatment with imatinib of a patient with CDH. This study examines the effect of antenatal imatinib administration on the pulmonary vasculature in a rat model of CDH. Pregnant rats were given nitrofen to induce CDH. Controls were given olive oil. Half of the CDH fetuses and half of the controls were treated with imatinib antenatally E17-E21, rendering four groups: Control, Control+Imatinib, CDH, and CDH+Imatinib. Lung sections were obtained for morphometry and immunohistochemistry, and protein was purified for Western blot. Effects of nitrofen and imatinib on Ki-67, caspase-3, PDGF-B, and PDGF receptors were analyzed. Imatinib significantly reduced medial wall thickness in pulmonary arteries of rats with CDH. It also normalized lumen area and reduced the proportion of fully muscularized arteries. Imatinib also caused medial thinning in the control group. Cell proliferation was increased in CDH, and this proliferation was significantly reduced by imatinib. PDGF-B and PDGFR-β were upregulated in CDH, and imatinib treatment resulted in a downregulation. PDGFR-α remained unchanged in CDH but was significantly downregulated by imatinib. Antenatal imatinib treatment reduces development of medial wall thickness and restores lumen area in pulmonary arteries in nitrofen-induced CDH. The mechanism is reduced cell proliferation. Imatinib is an interesting candidate for antenatal therapy for PH in CDH, but potential side effects need to be investigated and more specific targeting of PDGF signaling is needed.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…These differences were no longer detectable on day 21 (9). PDGF-A knockout leads to defective alveologenesis and is embryonically lethal (27).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia

Chang

Uggla²,

Österholm

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…13,14 To better understand the genetic factors contributing to CP, more susceptible genes are needed to be identified. PDGFRa was previously suggested to have a role in diaphragmatic hernia 15 and total anomalous pulmonary venous return (TAPVR). 16 A recently published article showed that disruption in Pdgf signaling in zebrafish caused craniofacial anomalies.…”

Section: Discussionmentioning

confidence: 99%

PDGFRa mutations in humans with isolated cleft palate

et al. 2012

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Isolated cleft palate (CP) is common in humans and has complex genetic etiologies. Many genes have been found to contribute to CP, but the full spectrum of genes remains unknown. PCR-sequencing of the entire coding regions and the 3 0 untranslated region (UTR) of the platelet-derived growth factor receptor alpha (PDGFRa) and the microRNA (miR), miR-140 identified seven novel single base-pair substitutions in the PDGFRa in 9/102 patients with CP (8.8%), compared with 5/500 ethnic-matched unaffected controls (1%) (the two-tailed P-valueo0.0001). Of these seven, four were missense mutations in the coding regions and three in the 3 0 UTR. Frequencies of four changes (three in coding, one in 3 0 UTR) were statistically different from those of controls (P-valueo0.05). The c.*34G4A was identified in 1/102 cases and 0/500 controls. This position is conserved in primates and located 10 bp away from a predicted binding site for the miR-140. Luciferase assay revealed that, in the presence of miR-140, the c.*34G4A significantly repressed luciferase activity compared with that of the wild type, suggesting functional significance of this variant. This is the first study providing evidence supporting a role of PDGFRa in human CP.

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Imbalance of Caveolin‐1 and eNOS Expression in the Pulmonary Vasculature of Experimental Diaphragmatic Hernia

Hofmann

Gosemann

Takahashi

et al. 2014

Birth Defects Research Pt B

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Abnormal platelet-derived growth factor signaling accounting for lung hypoplasia in experimental congenital diaphragmatic hernia

Cited by 23 publications

References 26 publications

Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia

Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia

PDGFRa mutations in humans with isolated cleft palate

Imbalance of Caveolin‐1 and eNOS Expression in the Pulmonary Vasculature of Experimental Diaphragmatic Hernia

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