Abstract
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 a-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.
| Original language | English |
|---|---|
| Pages (from-to) | 552-563 |
| Number of pages | 12 |
| Journal | American Journal of Respiratory Cell and Molecular Biology |
| Volume | 42 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2010 |
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Keywords
- Connective tissue growth factor
- Development
- Postnatal lung
- Transgenic
ASJC Scopus subject areas
- Cell Biology
- Pulmonary and Respiratory Medicine
- Molecular Biology
- Clinical Biochemistry
Cite this
Conditional overexpression of connective tissue growth factor disrupts postnatal lung development. / Wu, Shu; Platteau, Astrid; Chen, Shaoyi; McNamara, George; Whitsett, Jeffrey; Bancalari, Eduardo.
In: American Journal of Respiratory Cell and Molecular Biology, Vol. 42, No. 5, 01.05.2010, p. 552-563.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Conditional overexpression of connective tissue growth factor disrupts postnatal lung development
AU - Wu, Shu
AU - Platteau, Astrid
AU - Chen, Shaoyi
AU - McNamara, George
AU - Whitsett, Jeffrey
AU - Bancalari, Eduardo
PY - 2010/5/1
Y1 - 2010/5/1
N2 - 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 a-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.
AB - 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 a-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.
KW - Connective tissue growth factor
KW - Development
KW - Postnatal lung
KW - Transgenic
UR - http://www.scopus.com/inward/record.url?scp=77951644978&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951644978&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2009-0068OC
DO - 10.1165/rcmb.2009-0068OC
M3 - Article
C2 - 19541844
AN - SCOPUS:77951644978
VL - 42
SP - 552
EP - 563
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 5
ER -