Conditional overexpression of connective tissue growth factor disrupts postnatal lung development.
Connective tissue growth factor (CTGF) is a member of an emerging family of immediate-early gene products that coordinates complex biological processes during development, differentiation, and tissue repair. Overexpression of CTGF is associated with mechanical ventilation with high tidal volume and oxygen exposure in newborn lungs. However, the role of CTGF in postnatal lung development and remodeling is not well understood. In the present study, a double-transgenic mouse model was generated with doxycycline-inducible overexpression of CTGF in respiratory epithelial cells. Overexpression of CTGF from Postnatal Days 1-14 resulted in thicker alveolar septa and decreased secondary septal formation. This is correlated with increased myofibroblast differentiation and disorganized elastic fiber deposition in alveolar septa. Overexpression of CTGF also decreased alveolar capillary network formation. There were increased alpha-smooth muscle actin expression and collagen deposition, and dramatic thickening in the peribronchial/peribronchiolar and perivascular regions in the double-transgenic lungs. Furthermore, overexpression of CTGF increased integrin-linked kinase expression, activated its downstream signaling target, Akt, as well as increased mRNA expression of fibronectin. These data demonstrate that overexpression of CTGF disrupts alveologenesis and capillary formation, and induces fibrosis during the critical period of alveolar development. These histologic changes are similar to those observed in lungs of infants with bronchopulmonary dysplasia.
Wu
Shu
S
Department of Pediatrics, Division of Neonatology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA. swu2@med.miami.edu
Platteau
Astrid
A
Chen
Shaoyi
S
McNamara
George
G
Whitsett
Jeffrey
J
Bancalari
Eduardo
E
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002196:Capillaries / Q000254:growth & development; D002454:Cell Differentiation; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D000099200:Scaffold Protein ILK
D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK