KERATINOCYTE GROWTH-FACTOR AND EMBRYONIC RAT LUNG MORPHOGENESIS

We examined possible roles of keratinocyte growth factor (KGF) and hep atocyte growth factor (HGF) in lung morphogenesis. By polymerase chain reaction, transcripts for both KGF and its receptor were detected ear ly (rat gestational days 16 and 14, respectively) and their abundance increased during lung morphogenesis. To evaluate possible role of KGF in lung morphogenesis, day 14 lung explants were cultured in Dulbecco' s modified Eagle medium +10% fetal calf serum for 1 to 4 days in the p resence (5-50 ng/ml) or absence of KGF (control). KGF (at 25 and 50 ng /ml) induced a marked reduction in the number of terminal branches and distension of the distal epithelium into cyst-like structures. These effects of exogenous KGF were progressively diminished by increasing c oncentrations of anti-KGF (2-16 mu g/ml). Electron microscopic examina tion revealed that the epithelial cells of the cystic structures conta ined lamellar bodies, and were therefore type II cells and/or their pr ogenitors. Northern blot analysis showed higher expression of surfacta nt protein C (SP-C) mRNA (a marker for alveolar epithelial type II cel ls) in KGF-treated fetal lungs. In situ hybridization of the KGF-treat ed lungs revealed that the SP-C mRNA-expressing cells were arranged di stally in the form of linear arrays, a pattern distinctly different fr om that in control lungs. Acidic fibroblast growth factor, which also binds KGF receptors, in the presence of heparin mimicked the effect of KGF on branching. Transforming growth factor-beta(1) (TGF-beta 1) inh ibited branching of fetal lungs in culture, and this effect dominated over that induced by KGF. Blocking of endogenous HGF with antibodies o r addition of HGF to cultures of fetal lung explants had no significan t effect on branching or growth. In conclusion, KGF markedly influence s branching, and epithelial growth, differentiation, and patterning du ring lung morphogenesis.