Stimulation of lung growth in fetuses with lung hypoplasia leads to altered postnatal lung structure in sheep

Increased lung expansion in the fetus stimulates lung growth and is being trialed clinically to reverse severe fetal lung hypoplasia. Our aim was to examine the effects of increased fetal lung expansion in the presence of lung hypoplasia on lung structure in sheep at term and 8 weeks after birth. Lung hypoplasia was induced in 15 fetal sheep by continuous drainage of tracheal fluid, commencing at approximately 113 days of gestation (term, approximately 148 days). In 10 of these fetuses, tracheal obstruction (TO) was performed from 137-147 days of gestation (treated lung hypoplasia, TLH), while lung liquid drainage continued until term in the remaining 5 fetuses (untreated lung hypoplasia, ULH). Lung tissues were obtained from 5 TLH, 5 ULH, and 5 control lambs at birth, and from 5 TLH and 5 control lambs at 8 weeks after birth. At birth, alveolar number, surface area, and interalveolar wall thickness were not different between TLH and control lambs, whereas airspace diameter was greater in TLH lambs (72.7 +/- 3.0 microm) than in controls (58.4 +/- 4.3 microm). Diameters of airspaces were not different between ULH and control lambs; however, alveolar numbers and surface area were reduced, while interalveolar wall thickness was increased in ULH lambs compared to controls. At 8 weeks after birth, alveolar number (928.0 +/- 66.1 x 10(6)) and surface area (30.3 +/- 2.2 m(2)) in TLH lambs were lower, whereas interalveolar wall thickness (83.0 +/- 3.1 microm) was greater than in control lambs (2,263.6 +/- 261.6 x 10(6), 46.7 +/- 4.8 m(2), and 68.6 +/- 2.1 microm, respectively). Our data show that TO restores most aspects of lung structure to normal in fetuses with lung hypoplasia but leads to altered alveolar development. The presence of fewer, larger alveoli in postnatal TLH animals may predispose these animals to respiratory complications during later life.