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

Min Rong, Shaoyi Chen, Ronald Zambrano, Matthew R. Duncan, Gary Grotendorst, Shu Wu

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)136-144
Number of pages9
JournalPediatric Research
Volume80
Issue number1
DOIs
StatePublished - Jul 1 2016

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Connective Tissue Growth Factor
Catenins
Blood Vessels
Pathology
Lung
Bronchopulmonary Dysplasia
Pulmonary Hypertension
Autocrine Communication
Paracrine Communication
Alveolar Epithelial Cells
Cyclin D1
Dimethyl Sulfoxide
Fibronectins
Premature Infants
Transgenic Mice
Lung Diseases
Chronic Disease
Collagen
Down-Regulation
Placebos

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung. / Rong, Min; Chen, Shaoyi; Zambrano, Ronald; Duncan, Matthew R.; Grotendorst, Gary; Wu, Shu.

In: Pediatric Research, Vol. 80, No. 1, 01.07.2016, p. 136-144.

Research output: Contribution to journalArticle

Rong, Min ; Chen, Shaoyi ; Zambrano, Ronald ; Duncan, Matthew R. ; Grotendorst, Gary ; Wu, Shu. / Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung. In: Pediatric Research. 2016 ; Vol. 80, No. 1. pp. 136-144.
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AB - 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.

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