CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia.
The pathological hallmarks of bronchopulmonary dysplasia (BPD), one of the most common long-term pulmonary complications associated with preterm birth, include arrested alveolarization, abnormal vascular growth, and variable interstitial fibrosis. Severe BPD is often complicated by pulmonary hypertension characterized by excessive pulmonary vascular remodeling and right ventricular hypertrophy that significantly contributes to the mortality and morbidity of these infants. Connective tissue growth factor (CTGF) is a multifunctional protein that coordinates complex biological processes during tissue development and remodeling. We have previously shown that conditional overexpression of CTGF in airway epithelium under the control of the Clara cell secretory protein promoter results in BPD-like architecture in neonatal mice. In this study, we have generated a doxycycline-inducible double transgenic mouse model with overexpression of CTGF in alveolar type II epithelial (AT II) cells under the control of the surfactant protein C promoter. Overexpression of CTGF in neonatal mice caused dramatic macrophage and neutrophil infiltration in alveolar air spaces and perivascular regions. Overexpression of CTGF also significantly decreased alveolarization and vascular development. Furthermore, overexpression of CTGF induced pulmonary vascular remodeling and pulmonary hypertension. Most importantly, we have also demonstrated that these pathological changes are associated with activation of integrin-linked kinase (ILK)/glucose synthesis kinase-3β (GSK-3β)/β-catenin signaling. These data indicate that overexpression of CTGF in AT II cells results in lung pathology similar to those observed in infants with severe BPD and that ILK/GSK-3β/β-catenin signaling may play an important role in the pathogenesis of severe BPD.
Department of Pediatrics, Division of Neonatology, Univ. of Miami Miller School of Medicine, FL 33101, USA.
Shaoyi
S
Chen
Min
M
Rong
Astrid
A
Platteau
Dorothy
D
Hehre
Heather
H
Smith
Philip
P
Ruiz
Jeffrey
J
Whitsett
Eduardo
E
Bancalari
Shu
S
Wu
D000818:Animals; D000831:Animals, Newborn; D002467:Cell Nucleus / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D055370:Lung Injury / Q000150:complications* / Q000209:etiology*; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D011014:Pneumonia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism
C526318:CCN2 protein, mouse; D051176:beta Catenin; D055513:Connective Tissue Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
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