PULMONARY MALFORMATION IN TRANSGENIC MICE EXPRESSING HUMAN KERATINOCYTE GROWTH-FACTOR IN THE LUNG

Expression of human keratinocyte growth factor (KGF/FGF-7) was directe d to epithelial cells of the developing embryonic lung of transgenic m ice disrupting normal pulmonary morphogenesis during the pseudoglandul ar stage of development, By embryonic day 15.5 (E15.5), lungs of trans genic surfactant protein C (SP-C)-KGF mice resembled those of humans w ith pulmonary cystadenoma. Lungs were cystic, filling the thoracic cav ity, and were composed of numerous dilated saccules lined with glycoge n-containing columnar epithelial cells, The normal distribution of SP- C proprotein in the distal regions of respiratory tubules was disrupte d. Columnar epithelial cells lining the papillary structures stained v ariably and weakly for this distal respiratory cell marker, Mesenchyma l components were preserved in the transgenic mouse lungs, yet the arc hitectural relationship of the epithelium to the mesenchyme was altere d, SP-C-KGF transgenic mice failed to survive gestation to term, dying before E17.5. Culturing mouse fetal lung explants in the presence of recombinant human KGF also disrupted branching morphogenesis and resul ted in similar cystic malformation of the lung, Thus, it appears that precise temporal and spatial expression of KGF is likely to play a cru cial role in the control of branching morphogenesis during fetal lung development.