HEPATOCYTE GROWTH-FACTOR STIMULATES DNA-SYNTHESIS IN ALVEOLAR EPITHELIAL TYPE-II CELLS IN-VITRO

Hepatocyte growth factor (HGF) and its receptor, the product of c-MET proto-oncogene, are highly expressed in both fetal and adult lung, tho ugh their physiologic functions in the lung are largely unknown. In th e present study we examined whether alveolar type II cells in the lung are the target of HGF and whether HGF has any effects on growth of th ese cells. The alveolar epithelial type II cells were isolated from th e lungs of adult male Sprague-Dawley rats by elastase digestion, and t he cells were used to determine whether they express HGF and c-MET mRN As and whether recombinant HGF has any effect on their DNA synthesis i n primary culture. The effects were further compared with those induce d by epidermal growth factor (EGF), acidic fibroblast growth factor (a FGF), transforming growth factor-alpha (TGF-alpha), and transforming g rowth factor-beta(1) (TGF-beta(1)). Northern blot analysis and in situ hybridization revealed that type II cells express c-MET mRNA but not HGF mRNA. HGF stimulated [H-3]thymidine incorporation into type II cel ls in primary cultures. An increase was also seen in labeling index as determined by nuclear immunostaining of bromodeoxyuridine-incorporate d DNA. While aFGF (200 ng/ml) exerted an effect comparable to HGF (25 ng/ml) on DNA synthesis in type II cells, EGF (20 ng/ml) and TGF-alpha (100 ng/ml) had lesser effects. TGF-beta(1), a potent inhibitor of ep ithelial cell proliferation, at 0.25 to 2 ng/ml, did not inhibit HGF-i nduced [H-3]thymidine incorporation into type II cells. The results in dicate that HGF exerts its effects on type II cells as a potent mitoge n by a paracrine mode of action.