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Determination of alveolar epithelial cell phenotypes in fetal sheep: evidence for the involvement of basal lung expansion

Sharon J. Flecknoe, Megan J. Wallace, Richard Harding and Stuart B. Hooper

The factors that control the differentiation of alveolar epithelial cells (AECs) into type-I and type-II cells in vivo are largely unknown. As sustained increases in fetal lung expansion induce type-II AECs to differentiate into type-I cells, our aim was to determine whether reduced fetal lung expansion can induce type-I AECs to trans-differentiate into type-II AECs. Chronically catheterised fetal sheep were divided into two age-matched control groups and three experimental groups (n = 5 for each). The experimental groups were exposed to either: (1) 10 days of increased lung expansion induced by tracheal obstruction (TO), (2) 10 days of TO followed by 5 days of reduced lung expansion induced by lung liquid drainage (LLD), or (3) 10 days of TO followed by 10 days of LLD. Following 10 days of TO, 5 days of LLD reduced the proportion of type-I AECs from 89.4 ± 0.9 % to 68.4 ± 2.8 %, which was similar to control values (64.8 ± 0.5 %), and increased the proportion of type-II AECs from 1.9 ± 0.3 % to 21.9 ± 2.8 %, which remained below control values (33.4 ± 1.7 %). The same treatment increased surfactant protein (SP)-A, SP-B and SP-C mRNA levels (expressed as a percentage of control values) from 26.7 ± 6.0 %, 40.0 ± 7.3 % and 10.3 ± 1.8 % to 78.1 ± 10.3 %, 105.8 ± 12.7 % and 121.0 ± 14.1 %, respectively. Similar results were obtained after 10 days of LLD, which followed 10 days of TO. These results indicate that the phenotypes of type-I and type-II AECs are strongly influenced by the basal degree of lung expansion in fetal sheep. Furthermore, the coincident increase in type-II AEC proportions and SP mRNA levels in response to LLD suggests that type-I AECs can trans-differentiate into functional type-II cells, and hence are not terminally differentiated.

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