Insulin-like growth factor-I gene expression in three models of accelerated lung growth.
OBJECTIVE
We have learned previously that in utero tracheal ligation reverses the structural and physiological effects of surgically created congenital diaphragmatic hernia. In addition, we have discovered that postnatal lung growth similarly can be accelerated using liquid-based airway distension with perfluorocarbon. Another model of accelerated lung growth is that of compensatory growth seen after neonatal pneumonectomy. In all of these models, growth has occurred because of an increase in alveolar number rather than enlargement of preexisting alveoli. However, the molecular mechanisms underlying these processes remain unknown. The purpose of this study was to determine if gene expression could be altered by changes in physical forces in the prenatal and postnatal lung.


METHODS
The three models of accelerated lung growth studied were the following: (1) The prenatal group, consisted of fetal lambs (n = 12) that underwent the surgical creation of a left diaphragmatic hernia at 90 days' gestation. Six of these animals also underwent simultaneous tracheal ligation. (2) The PFC group consisted of five neonatal animals that underwent isolation of the superior segment of the right upper lobe, with intrabronchial distension with perfluorocarbon to 7 to 10 mm Hg pressure for a 3-week period. (3) The postpneumonectomy group consisted of four neonatal animals that underwent left pneumonectomy. In the fetal study, lungs were retrieved at term (130 days), and in the postnatal study, lungs were retrieved 3 weeks after initial intervention. In all cases, RNA was extracted from snap-frozen lung samples and Northern blot analysis performed.


RESULTS
Insulinlike growth factor-I, insulinlike growth factor-II, and vascular endothelial growth factor gene expression were analyzed by densitometry. Insulinlike growth factor-I gene expression was found to be decreased in association with experimental diaphragmatic hernia (P = .005), but restored to normal with tracheal ligation. Insulinlike growth factor-I gene expression was significantly increased in both postnatal models of accelerated lung growth (P = .022, P = .016). No significant differences were found in insulinlike growth factor-II or vascular endothelial growth factor gene expression.


CONCLUSIONS
The authors conclude from these preliminary data that (1) insulin like growth factor-I gene expression is reduced in experimental fetal diaphragmatic hernia and restored to normal by tracheal ligation, and (2) insulinlike growth factor-I gene expression is increased in both the liquid-based airway distension and postpneumonectomy models of accelerated postnatal lung growth. The authors speculate that all of these manipulations exploit a natural pathway essential for normal lung growth.
Department of Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
K K
KK
Nobuhara
J W
JW
DiFiore
J C
JC
Ibla
A M
AM
Siddiqui
M L
ML
Ferretti
D O
DO
Fauza
J J
JJ
Schnitzer
J M
JM
Wilson
D000818:Animals; D015152:Blotting, Northern; D004587:Electrophoresis, Agar Gel; D005314:Embryonic and Fetal Development; D016228:Endothelial Growth Factors / Q000378:metabolism; D005315:Fetal Diseases / Q000601:surgery; D005466:Fluorocarbons / Q000008:administration & dosage; D006548:Hernia, Diaphragmatic / Q000601:surgery; D065630:Hernias, Diaphragmatic, Congenital; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics; D008026:Ligation; D008168:Lung / Q000196:embryology / Q000254:growth & development*; D008222:Lymphokines / Q000378:metabolism; D011013:Pneumonectomy; D012313:RNA / Q000032:analysis; D012756:Sheep; D014132:Trachea / Q000601:surgery; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D005466:Fluorocarbons; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D012313:RNA