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Coordination of growth and differentiation in the fetal lung
H C Nielsen1, W O Kirk, N Sweezey
1Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts.
Insights
Androgens, like dihydrotestosterone (DHT), delay male fetal lung differentiation by extending fetal lung growth. This study reveals a reciprocal link between fetal lung growth and differentiation control.
Area of Science:
- Developmental Biology
- Endocrinology
- Pulmonary Medicine
Background:
- Male fetal lung surfactant synthesis is delayed compared to females, potentially due to androgen influence.
- Androgens may prolong fetal lung growth, consequently delaying differentiation.
Purpose of the Study:
- To investigate the hypothesis that androgens delay male fetal lung differentiation by extending fetal lung growth.
- To elucidate the relationship between fetal lung growth and differentiation control.
Main Methods:
- In vivo studies involving pregnant rats treated with dihydrotestosterone (DHT).
- Measurement of fetal lung wet weight, dry weight, DNA, and protein concentrations.
- Isolation and in vitro culture of fetal lung type II cells and fibroblasts for analysis of cell proliferation and differentiation markers.
Main Results:
- DHT treatment significantly increased fetal lung weight, DNA, and protein content.
- DHT increased the number of isolated type II cells and fibroblasts.
- In vitro, DHT stimulated fibroblast DNA synthesis and increased type II cell proliferation while decreasing surfactant (disaturated phosphatidylcholine) synthesis.
Conclusions:
- Androgens, such as DHT, induce fetal lung growth and delay differentiation.
- The control mechanisms for fetal lung growth and differentiation are reciprocally linked.
- DHT's dual action highlights a complex interplay between growth and differentiation pathways in the developing lung.
Abstract:
The male fetal lung begins to synthesize surfactant later in gestation than the female. This delay appears to be caused by androgens. We hypothesized that male fetal lung differentiation is delayed as a consequence of an extended phase of growth which is elicited by androgens. We observed that in vivo fetal lung protein synthesis relative to DNA synthesis peaked earlier in gestation in the female fetal lung and that this event was synchronous with the onset of differentiation. Pregnant rats were treated with dihydrotestosterone (DHT) during pregnancy, and fetal lung growth parameters were measured. Lung wet weight, dry weight, and DNA and protein concentrations were significantly elevated by DHT treatment. Type II cells and fibroblasts were isolated from lungs of DHT-treated fetuses. The number of total cells recovered was increased by 30%; the number of type II cells recovered was increased by 87%; and the number of fibroblasts recovered was increased by 42%. The type II cells which were recovered exhibited increased incorporation of [3H]thymidine into DNA and a reduced ratio of radiolabeled protein to radiolabeled DNA compared to that of cells from control lungs. Further studies were done in vitro with fibroblasts and type II cells isolated from untreated fetal rat lungs. Treatment of the fibroblasts with DHT during culture caused an increase in thymidine incorporation into DNA. This effect was not blocked by simultaneous treatment with cortisol, which normally causes reduced DNA synthesis and induces fibroblast differentiation. Treatment of the type II cells with DHT in culture caused a dose-dependent increase in cell number but a decrease in synthesis of disaturated phosphatidylcholine. These studies provide more direct evidence of the interrelationships between the control of growth and the control of differentiation in the fetal lung. DHT, a signal which delays the onset of expression of differentiation, also induces growth. We conclude that the controls of growth and of differentiation of the fetal lung are reciprocally linked.