KERATINOCYTE GROWTH-FACTOR STIMULATES CFTR-INDEPENDENT FLUID SECRETION IN THE FETAL LUNG IN-VITRO

Keratinocyte growth factor (KGF) caused cystic dilation of mouse fetal lung explants in vitro, markedly increasing the luminal volume of lun g buds and disrupting branching morphogenesis. Effects of KGF were dos e dependent, were detected within 4 h of treatment, and were blocked b y cycloheximide but not by actinomycin D, indicating that de novo prot ein synthesis mediated the response. Effects of KGF were inhibited by bumetanide, an inhibitor of the Na+-K+-Cl- cotransporter, and ouabain, an inhibitor of Na+-K+-ATPase. KGF stimulated fluid secretion equally in lung buds from cystic fibrosis transmembrane conductance regulator s (CFTR) -/- and wild-type embryos, indicating that the effects were m ediated by CFTR-independent Cl- transport. Microelectrode studies demo nstrated that, whereas KGF did not acutely alter the transepithelial p otential difference (PD) across the respiratory epithelium, the PD dec reased while luminal volume increased during chronic exposure. KGF inh ibited expression of alpha-subunit of epithelial Na+ channel (alpha-EN aC) mRNA, suggesting that KGF may inhibit Na+ absorption, which may co ntribute to KGF-induced fluid accumulation. KGF-induced fluid accumula tion is driven by CFTR-independent Cl- transport and associated with d ecreased expression of alpha-ENaC.