I. Caniggia et al., INHIBITION OF FIBROBLAST GROWTH BY EPITHELIAL-CELLS IN FETAL-RAT LUNG, American journal of respiratory cell and molecular biology, 13(1), 1995, pp. 91-98
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-epit
helial 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 adva
ncing gestation. Conditioned medium of epithelial cells from the canal
icular 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-c
onditioned medium. The response of fibroblasts to this epithelial cell
-derived growth-inhibitory activity was organ specific but not gestati
on dependent. The inhibitory effect of epithelial cell-conditioned med
ium on fibroblast proliferation was overcome by the addition of > 2% f
etal bovine serum. The inhibition was not mediated by prostaglandins b
ecause 50 mu M ibuprofen, a prostaglandin synthase inhibitor, did not
block the elaboration of the inhibitory activity by fetal lung epithel
ial cells. Partial characterization of the fibroblast growth-inhibitor
y activity in epithelial cell-conditioned medium showed that it was tr
ypsin labile, heat and acid insensitive, and lipid extractable. Its mo
lecular 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 inhib
itory 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 result
s are compatible with a role for epithelial cells in regulating mesenc
hymal condensation at late fetal rat gestation.