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1 Section of Pediatric Surgery, Department of Surgery, Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania 17033; and 2 The Floating Hospital for Children at New England Medical Center, Boston, Massachusetts 02111
Studies on lung morphogenesis have indicated a
role of homeobox
(Hox) genes in the regulation of
lung development. In the present study, we attempted to modulate the
synthesis of Hoxb5 protein in cultured murine fetal lungs after
mechanical or chemical stimuli. Murine fetuses at gestational
day 14 (GD14) were removed from
pregnant CD-1 mice, and lungs were excised and cultured for 7 days in
BGJb media. The experimental groups were
1) untreated, unligated;
2) tracheal ligation;
3) supplemented media with either epidermal growth factor (EGF; 10 ng/ml), transforming growth factor (TGF)-
1 (2 ng/ml), dexamethasone (10 nM), EGF+TGF-1, or
EGF+TGF-1+dexamethasone. After 3 or 7 days, the cultured lungs were
compared with in vivo lungs. Immunoblotting signals at 3 days in
culture were stronger than those at 7 days. Western blot analyses
showed that ligation, EGF, TGF-1, and EGF+TGF-1 downregulated
Hoxb5 protein to ~20-70% of Hoxb5 protein levels in unligated,
untreated cultured lungs. Furthermore, dexamethasone alone or in
combination with EGF and TGF-1 downregulated Hoxb5 protein by
>90% (P < 0.05) signal
strength, similar to that seen in GD19 or in neonatal lungs.
Immunostaining showed that Hoxb5 protein was expressed strongly in the
lung mesenchyme at early stages in gestation. However, by GD19 and in
neonates, it was present only in specific epithelial cells. A
persistent level of Hoxb5 protein in the mesenchyme after EGF or
TGF-1 treatments or tracheal ligation was noted. Hoxb5 protein was
significantly downregulated by EGF+TGF-1, and it was least in lungs
after dexamethasone or EGF+TGF-1+dexamethasone treatment. The
decrease in Hoxb5 protein was significant only in the groups with
dexamethasone added to the media. Thus immunostaining results parallel
those of immunoblotting. The degree of Hoxb5 downregulation by
dexamethasone or EGF+TGF-1+dexamethasone was similar to that seen in
vivo in very late gestation, which correlated to the advancing
structural development of the lung.
lung development; epidermal growth factor; transforming growth
factor-1; mesenchyme; homeobox b5; glucocorticoid
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