title: Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Batchelor Children's Research Institute, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Rong
authors.affiliation: Department of Pediatrics, Division of Neonatology, Batchelor Children's Research Institute, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Division of Neonatology, Batchelor Children's Research Institute, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Zambrano
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Duncan
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Grotendorst
authors.affiliation: Department of Pediatrics, Division of Neonatology, Batchelor Children's Research Institute, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Wu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D018893:Bronchoalveolar Lavage; D001997:Bronchopulmonary Dysplasia / Q000188:drug therapy / Q000235:genetics; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor / Q000235:genetics*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005353:Fibronectins / Q000378:metabolism; D018496:Hyperoxia / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000473:pathology; D011744:Pyrimidinones / Q000494:pharmacology; D015398:Signal Transduction; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C526318:CCN2 protein, mouse; C495267:CTNNB1 protein, mouse; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C509983:Dixdc1 protein, mouse; D005353:Fibronectins; C492448:ICG 001; D047908:Intracellular Signaling Peptides and Proteins; D011744:Pyrimidinones; D051176:beta Catenin; D055513:Connective Tissue Growth Factor