Abstract
Bronchial asthma is an inflammatory disease characterized by chronic intermittent bronchoconstriction. A key feature of the disease is structural changes in the airway wall (airway remodeling) consistent with tissue growth and chronic wound healing including angiogenesis. The epithelium directs mesenchymal processes during both embryogenesis and wound healing, and thus we hypothesized that the bronchial epithelium plays a critical role in directing angiogenesis. To study angiogenesis in the airways, we have developed a three-dimensional (3-D) in vitro model of the airway mucosa that consists of normal differentiated human bronchial epithelial cells (NHBE), normal human lung fibroblasts (NHLF), and human umbilical vein endothelial cells (HUVEC). The HUVEC are coated on dextran beads and suspended in a fibrin gel approximately 2 mm beneath a confluent monolayer of NHLF which are just beneath the confluent monolayer of differentiated NHBE. In the presence of fibroblasts, visible capillaries reaching lengths of up to 1 mm sprout from the HUVEC-coated beads. Over 11 days in culture, the bronchial epithelium produces transforming growth factor-β2 (TGFβ2, 60 pg/ml), significantly increases vascular endothelial growth factor (VEGF) more than 6-fold to a concentration of 1.85 ng/ml, but does not significantly impact total network formation. Exogenous TGFβ2 stimulates VEGF production in a dose-dependent fashion (0-400 pg/ml) through a MAPK-dependent pathway, but also inhibits capillary network formation. We conclude that the bronchial epithelium produces biologically relevant concentrations of VEGF and TGFβ2 in a 3-D model of the airway mucosa that may be useful in probing mechanisms of angiogenesis in asthma.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 141-148 |
| Number of pages | 8 |
| Journal | Pulmonary Pharmacology and Therapeutics |
| Volume | 20 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 1 2007 |
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Keywords
- 3-dimensional
- Airway mucosa
- Angiogenesis
- Asthma
- Epithelium
- Fibrin gel
- In vitro model
- TGFbeta
- U0126
- VEGF
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Biochemistry, medical
- Pharmacology (medical)
Cite this
A three-dimensional in vitro model of angiogenesis in the airway mucosa. / Thompson, H. Garrett; Truong, David T.; Griffith, Craig K.; George, Steven.
In: Pulmonary Pharmacology and Therapeutics, Vol. 20, No. 2, 01.04.2007, p. 141-148.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A three-dimensional in vitro model of angiogenesis in the airway mucosa
AU - Thompson, H. Garrett
AU - Truong, David T.
AU - Griffith, Craig K.
AU - George, Steven
PY - 2007/4/1
Y1 - 2007/4/1
N2 - Bronchial asthma is an inflammatory disease characterized by chronic intermittent bronchoconstriction. A key feature of the disease is structural changes in the airway wall (airway remodeling) consistent with tissue growth and chronic wound healing including angiogenesis. The epithelium directs mesenchymal processes during both embryogenesis and wound healing, and thus we hypothesized that the bronchial epithelium plays a critical role in directing angiogenesis. To study angiogenesis in the airways, we have developed a three-dimensional (3-D) in vitro model of the airway mucosa that consists of normal differentiated human bronchial epithelial cells (NHBE), normal human lung fibroblasts (NHLF), and human umbilical vein endothelial cells (HUVEC). The HUVEC are coated on dextran beads and suspended in a fibrin gel approximately 2 mm beneath a confluent monolayer of NHLF which are just beneath the confluent monolayer of differentiated NHBE. In the presence of fibroblasts, visible capillaries reaching lengths of up to 1 mm sprout from the HUVEC-coated beads. Over 11 days in culture, the bronchial epithelium produces transforming growth factor-β2 (TGFβ2, 60 pg/ml), significantly increases vascular endothelial growth factor (VEGF) more than 6-fold to a concentration of 1.85 ng/ml, but does not significantly impact total network formation. Exogenous TGFβ2 stimulates VEGF production in a dose-dependent fashion (0-400 pg/ml) through a MAPK-dependent pathway, but also inhibits capillary network formation. We conclude that the bronchial epithelium produces biologically relevant concentrations of VEGF and TGFβ2 in a 3-D model of the airway mucosa that may be useful in probing mechanisms of angiogenesis in asthma.
AB - Bronchial asthma is an inflammatory disease characterized by chronic intermittent bronchoconstriction. A key feature of the disease is structural changes in the airway wall (airway remodeling) consistent with tissue growth and chronic wound healing including angiogenesis. The epithelium directs mesenchymal processes during both embryogenesis and wound healing, and thus we hypothesized that the bronchial epithelium plays a critical role in directing angiogenesis. To study angiogenesis in the airways, we have developed a three-dimensional (3-D) in vitro model of the airway mucosa that consists of normal differentiated human bronchial epithelial cells (NHBE), normal human lung fibroblasts (NHLF), and human umbilical vein endothelial cells (HUVEC). The HUVEC are coated on dextran beads and suspended in a fibrin gel approximately 2 mm beneath a confluent monolayer of NHLF which are just beneath the confluent monolayer of differentiated NHBE. In the presence of fibroblasts, visible capillaries reaching lengths of up to 1 mm sprout from the HUVEC-coated beads. Over 11 days in culture, the bronchial epithelium produces transforming growth factor-β2 (TGFβ2, 60 pg/ml), significantly increases vascular endothelial growth factor (VEGF) more than 6-fold to a concentration of 1.85 ng/ml, but does not significantly impact total network formation. Exogenous TGFβ2 stimulates VEGF production in a dose-dependent fashion (0-400 pg/ml) through a MAPK-dependent pathway, but also inhibits capillary network formation. We conclude that the bronchial epithelium produces biologically relevant concentrations of VEGF and TGFβ2 in a 3-D model of the airway mucosa that may be useful in probing mechanisms of angiogenesis in asthma.
KW - 3-dimensional
KW - Airway mucosa
KW - Angiogenesis
KW - Asthma
KW - Epithelium
KW - Fibrin gel
KW - In vitro model
KW - TGFbeta
KW - U0126
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=33751159859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33751159859&partnerID=8YFLogxK
U2 - 10.1016/j.pupt.2005.12.001
DO - 10.1016/j.pupt.2005.12.001
M3 - Article
C2 - 16414296
AN - SCOPUS:33751159859
VL - 20
SP - 141
EP - 148
JO - Pulmonary Pharmacology and Therapeutics
JF - Pulmonary Pharmacology and Therapeutics
SN - 1094-5539
IS - 2
ER -