Changes in lung structure and cellular division induced by tracheal obstruction in fetal sheep

Increased expansion of the fetal lung, caused by obstruction of the fetal trachea, is a potent stimulus for growth and structural development of the fetal lung. Our aim was to analyze the changes in lung structure induced by fetal tracheal obstruction and to identify cell types that contribute to the growth response. Fetal sheep were exposed to 2, 4, or 10 days of tracheal obstruction (TO) and on day 128 of gestation (term 147 d), mere injected with H-3-thymidine 8 hours before tissues were collected. The right lung was fixed at 20 cm H2O and prepared for stereological and autoradiographic analysis. Alveolar wall thickness (7.8 +/- 0.3 mu m vs 5.5 +/- 0.4 mu m) and percent tissue space (27.9 +/- 0.9% vs 21.4 +/- 2.8%) were increased at 2 days of TO, but were not different from control at 4 and 10 days. The luminal surface area of the right lung increased gradually from 2.4 +/- 0.2 m(2)/kg in control fetuses to 3.6 +/- 0.4 m(2)/kg following 10 days of 10 and this increase was accompanied by an increase in alveolar number (control: 808 x 10(6) +/- 81.9 x 10(6) vs 10d obstruct: 1254 x 10(6) +/- 63 x 10(6)). Alveolar diameter increased at 2 days of 10 (51.8 +/- 1.4 mu m vs 43.8 +/- 1.9 mu m), but was not increased further at 4 or 10 days. The percentage of dividing cells was increased at 2 days of TO (12.64 +/- 3.39% vs 1.73 +/- 0.31%), remained elevated at 4 days (5.01 +/- 0.27%), but had returned to control by day 10. The increase at 2 days was due to division of type II epithelial cells, fibroblasts, and endothelial cells. We conclude that increased expansion of the fetal lung induces time-dependent changes in lung structure and cell division rates; these include a transient increase in alveolar wall thickness, a rapid increase in alveolar number, and a gradual increase in luminal surface area. The latter is probably caused by an increase in alveolar number rather than an increase in the alveolar size.