INHIBITION OF FIBROBLAST GROWTH BY EPITHELIAL-CELLS IN FETAL-RAT LUNG

The canalicular and saccular stages of rat lung development are marked by thinning of mesenchymal tissue. Because cell-cell interactions are important for normal fetal lung development, we investigated whether this regression of mesenchymal tissue is controlled by fibroblast-epithelial cell interactions. Using flow cytometry, thymidine uptake into DNA, and cell doubling time, we observed an increase in the proportion of lung fibroblasts in the G(0)/C-1 phase of the cell cycle with advancing gestation. Conditioned medium of epithelial cells from the canalicular stage of lung development, but not from the pseudoglandular and saccular stages, inhibited fetal lung fibroblast proliferation. Fetal lung epithelial cell growth was not affected by the epithelial cell-conditioned medium. The response of fibroblasts to this epithelial cell-derived growth-inhibitory activity was organ specific but not gestation dependent. The inhibitory effect of epithelial cell-conditioned medium on fibroblast proliferation was overcome by the addition of > 2% fetal bovine serum. The inhibition was not mediated by prostaglandins because 50 mu M ibuprofen, a prostaglandin synthase inhibitor, did not block the elaboration of the inhibitory activity by fetal lung epithelial cells. Partial characterization of the fibroblast growth-inhibitory activity in epithelial cell-conditioned medium showed that it was trypsin labile, heat and acid insensitive, and lipid extractable. Its molecular weight appears to be > 3.5 and < 12.5 kD. Transforming growth factor-beta(1) and surfactant proteins B and C did not mimic the inhibitory effect of epithelial cell-conditioned medium. These data suggest that fetal lung epithelial cells elaborate a hydrophobic polypeptide that inhibits fetal lung fibroblast proliferation in vitro. The results are compatible with a role for epithelial cells in regulating mesenchymal condensation at late fetal rat gestation.