In the fetal lung EGF-R activation stimulates the development of surfactant production via fibroblast-type II cell communication. EGF-R expression during fetal lung maturation is cell specific and developmentally regulated. Fetal rat lung fibroblasts but not type II cells exhibit a gestational increase in EGF-R that peaks at the time of maximum cell-cell communication stimulating surfactant synthesis. We hypothesize that cell specific EGF-R activation is important for the development of fibroblast-type II cell communication leading to surfactant production. We transducted immature rat lung fibroblasts (fetal days 17 and 19) which inherently express low (D17) and moderate (D19) levels of EGF-R activity, using retroviral constructs expressing wild type EGF-R (WT) or mutant EGF-R (MUT, lacking the intracellular signaling domain). Transduction efficiency was measured by specific EGF-R binding, which increased between 4- (D19) and 47-fold (D17) in transducted cells compared to controls. Fibroblast conditioned medium (FCM) was collected from transducted cells with or without EGF pretreatment, and its ability to stimulate choline incorporation into disaturated phosphatidylcholine (DSPC) studied in MLE12 cells (mouse lung epithelial cell line expressing surfactant). Choline incorporation into DSPC was stimulated by FCM obtained from D19 control cells treated with EGF (138±12%) and from both D17 and D19 fibroblasts transducted with WT EGF-R, but not by FCM from cells transducted with MUT EGF-R (Table shows% stimulation from control, mean±SEM). However, EGF-R activation with EGF downregulated this stimulatory effect (Table). These data show that increased EGF-R expression in fetal lung fibroblasts activates fibroblast-epithelial cell communication stimulating surfactant synthesis. Immature fibroblasts with low EGF-R levels may possess intact intracellular signal transduction pathways which can be utilized by the ectopically expressed WT EGF-R. Lack of stimulation with MUT EGF-R indicates a receptor mediated mechanism. EGF treatment of transducted cells may cause EGF-R downregulation and loss of signal transduction stimulating cell-cell communication. We conclude that EGF-R regulates development of cell-cell communication in fetal lung maturation.

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