Conditional Overexpression of Connective Tissue Growth Factor Disrupts Postnatal Lung Development

Wu, Shu; Platteau, Astrid; Chen, Shaoyi; McNamara, George; Whitsett, Jeffrey A.; Bancalari, Eduardo

doi:10.1165/rcmb.2009-0068oc

Cited by 57 publications

(48 citation statements)

References 55 publications

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“…CTGF has recently been shown to be sufficient (30) and required for murine hyperoxia-induced neonatal lung injury (2). We tested whether CTGF could be responsible for GSK-3␤/␤-catenin-mediated myofibroblastic differentiation in our model, as well in infants with BPD.…”

Section: Transduction Of Mscs With Gsk-3␤ S9a a Nonphosphorylatable mentioning

confidence: 99%

Glycogen synthase kinase-3β/β-catenin signaling regulates neonatal lung mesenchymal stromal cell myofibroblastic differentiation

Popova¹,

Bentley²,

Anyanwu

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Section: Transduction Of Mscs With Gsk-3␤ S9a a Nonphosphorylatable mentioning

confidence: 99%

Glycogen synthase kinase-3β/β-catenin signaling regulates neonatal lung mesenchymal stromal cell myofibroblastic differentiation

Popova¹,

Bentley²,

Anyanwu

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Multiple studies have examined the potential role of CTGF in experimental BPD and demonstrated that increased CTGF expression is associated with chronic hyperoxia as well as mechanical ventilationinduced lung injury in neonatal rodents (6-10). Recent studies from our laboratory utilizing genetic gain-of-function and biological loss-of-function approaches have provided compelling evidence that a novel signaling network orchestrated by CTGF plays an important role in BPD pathogenesis (6,11,12). In our novel transgenic mouse model, targeted overexpression of CTGF in alveolar type II epithelial (AT II) cells induces the pathological hallmarks of severe BPD, including decreased alveolar and vascular development and increased vascular remodeling and PH (12).…”

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confidence: 99%

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

et al. 2016

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Background: Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants. Connective tissue growth factor (CTGF) plays an important role in tissue development and remodeling. We have previously shown that targeted overexpression of CTGF in alveolar type II epithelial cells results in BPD-like pathology and activates β-catenin in neonatal mice. Methods: Utilizing this transgenic mouse model and ICG001, a specific pharmacological inhibitor of β-catenin, we tested the hypothesis that β-catenin signaling mediates the effects of CTGF in the neonatal lung. Newborn CTGF mice and control littermates received ICG001 (10 mg/kg/dose) or placebo (dimethyl sulfoxide, equal volume) by daily i.p. injection from postnatal day 5 to 15. Alveolarization, vascular development, and pulmonary hypertension (PH) were analyzed. results: Administration of ICG001 significantly downregulated expression of cyclin D1, collagen 1a1, and fibronectin, which are the known target genes of β-catenin signaling in CTGF lungs. Inhibition of β-catenin signaling improved alveolar and vascular development and decreased pulmonary vascular remodeling. More importantly, the improved vascular development and vascular remodeling led to a decrease in PH. conclusion: β-Catenin signaling mediates the autocrine and paracrine effects of CTGF in the neonatal lung. Inhibition of CTGF-β-catenin signaling may provide a novel therapy for BPD. INTRODUCTIONBronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants (1). Over the past four decades, the incidence of this disease has significantly increased as a result of improved survival of extremely-low-birthweight infants (2). The pathology of BPD is increasingly being recognized as a developmental arrest of the immature lung caused by injurious stimuli such as mechanical ventilation, oxygen exposure, and intrauterine or postnatal infections. Larger and simplified alveoli, decreased vascular growth, and variable interstitial fibrosis are the key pathological features observed in lungs of infants who died of BPD (1). The combination of decreased vascular growth and excessive pulmonary vascular remodeling leads to pulmonary hypertension (PH) which significantly contributes to the morbidity and mortality of these infants (3). Yet, the underlying cellular and molecular mechanisms are poorly defined, and there is no effective therapy.Connective tissue growth factor (CTGF) is a matricellular protein that plays an important role in tissue development and remodeling (4). Recent studies have highlighted the potential role of CTGF in BPD development and progression. The clinical association of CTGF with BPD is best established by studies demonstrating increased CTGF concentrations in bronchoalveolar lavage fluid from preterm infants developing BPD (5) and increased CTGF expression in lung tissues of infants who died of BPD (6). Multiple studies have examined the potential role of CTGF in experimental BPD and demonstrated that increased CTG...

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“…Septal thinning is accompanied by remodeling of the capillary network with a reduction in septal interstitial extracellular matrix proteins and closer apposition between capillaries and the type-1 epithelium (9). Septal thickening that accompanied overexpression of connective tissue growth factor during P1-P14 seemed to inhibit alveolar capillary formation (10). Understanding the thinning process is important because thickened walls are observed in mechanically ventilated lungs of children (11) and baboons (12) with bronchopulmonary dysplasia (BPD).…”

mentioning

confidence: 99%

Fibroblasts Expressing PDGF-Receptor-Alpha Diminish During Alveolar Septal Thinning in Mice

McGowan

McCoy

2011

Pediatr Res

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In mice, secondary alveolar septal formation primarily occurs during a brief postnatal period and is accompanied by transient expansion of the interstitial lung fibroblast (LF) population. PDGF-A, which solely signals through PDGF-receptor-alpha (PDGF-R␣), is required for expansion, but the receptor's relevant downstream targets remain incompletely defined. We have evaluated the proliferation, apoptosis, and differential response to the selective protein tyrosine kinase inhibitor, imatinib, by pdgfr␣-expressing LF (pdgfr␣-LF) and compared them with their nonexpressing LF counterparts. Our objective was to determine whether diminished signaling through PDGF-R␣-mediated pathways regulates the decline in myofibroblasts, which accompanies septal thinning and ensures more efficient alveolar gas exchange. Using quantitative stereology and flow cytometry at postnatal d 12 and 14, we observed that imatinib caused a selective suppression of proliferation and an increase in apoptosis. The number of the alpha smooth muscle actin (␣SMA) producing pdgfr␣-LF was also reduced. Using cultures of neonatal mouse LF, we showed that imatinib did not suppress PDGF-R␣ gene expression but reduced PDGF-A-mediated Akt phosphorylation, potentially explaining the increase in apoptosis. Our findings are relevant to bronchopulmonary dysplasia in which positive pressure ventilation interferes with myofibroblast depletion, septal thinning, and capillary maturation.

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Conditional Overexpression of Connective Tissue Growth Factor Disrupts Postnatal Lung Development

Cited by 57 publications

References 55 publications

Glycogen synthase kinase-3β/β-catenin signaling regulates neonatal lung mesenchymal stromal cell myofibroblastic differentiation

Glycogen synthase kinase-3β/β-catenin signaling regulates neonatal lung mesenchymal stromal cell myofibroblastic differentiation

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

Fibroblasts Expressing PDGF-Receptor-Alpha Diminish During Alveolar Septal Thinning in Mice

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