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

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. 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...

Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells

“…In a broader, more fundamental context, Acta2 [32,33], Col1a1 [34], and Survivin [35] have all been previously identified as direct or indirect targets of the CBP/β-catenin signaling pathway and associated with a proliferative and pro-fibrotic phenotype which characterizes activated PSCs [2][3][4][22][23][24]. Furthermore, Ppar-γ, a nuclear receptor which is associated with PSC quiescence [4,22,25,26], is known to have anti-inflammatory/anti-fibrotic activity [36] and should compete with β-catenin for binding to CBP's N-terminal region, thereby phenocopying ICG-001 antagonism of CBP/β-catenin binding and associated signaling [37].…”

Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia

“…The inhibition of CTNNB1 signaling has also been documented to protect against alveolar and vascular pathology in neonatal mouse lungs driven by connective tissue growth factor (CTGF) (452), where overexpression of CTGF in mouse lung epithelial cells (with the conditional, inducible Sftpc-rtTA driver line) caused alveolar simplification and reduced vascular density. Inhibition of CTNNB1 signaling with ICG001 limited the effects of CTGF overexpression on lung alveolar and vascular structure, possibly by normalizing cylin D1 (CCND1), fibronectin (FN1), and collagen I␣ 1 (COL1A1) expression.…”

“…In this key study from Parviz Minoo and coworkers, progenitors of secondary crest myofibroblasts were demonstrated to be developmentally committed in the early lung mesoderm. The related observation that homeobox protein (HOX) transcription factors regulate a WNT2/WNT2b/BMP4 signaling axis in early lung development also highlighted HOX transcription factors as potentially (216,440,558) and WNT target genes (452) have been identified in the context of lung development and WNT proteins have been suggested to be maternally delivered to nursing neonates (360,361). Furthermore, several physiological effects have been ascribed to WNT signaling, including the regulation of 1) alveolar type (AT)II cell expansion, 2) transdifferentiation of ATII cells to ATI cells (159,162), and 3) myofibroblast progenitor differentiation (288).…”

“…Fig.1. Recently described roles for WNT/CTNNB1 activity in late lung development: schematic illustration integrating several recently identified functions of WNT/CTNNB1 signaling in late lung development, where WNT regulators(216,440,558) and WNT target genes(452) have been identified in the context of lung development and WNT proteins have been suggested to be maternally delivered to nursing neonates(360,361). Furthermore, several physiological effects have been ascribed to WNT signaling, including the regulation of 1) alveolar type (AT)II cell expansion, 2) transdifferentiation of ATII cells to ATI cells(159,162), and 3) myofibroblast progenitor differentiation(288).…”

Connective tissue growth factor dependent collagen gene expression induced by MAS agonist AR234960 in human cardiac fibroblasts

“…CTGF regulates fibroblast proliferation, collagen synthesis and apoptosis, processes which accelerate cardiac fibrosis in pathological conditions such as diabetes or ischemic heart disease [ 6 ]. CTGF promoted myofibroblast differentiation [ 7 ] may underlie multiple diseases including renal [ 8 ] lung [ 9 ] and cardiac fibrosis in diabetes [ 10 ]. Although the role of CTGF in developmental biology and cancer has been widely studied, its regulation in cardiac biology is not well characterized.…”