ANTI-BOMBESIN MONOCLONAL-ANTIBODIES MODULATE FETAL MOUSE LUNG GROWTH AND MATURATION INUTERO AND IN ORGAN-CULTURES

Fetal pulmonary neuroendocrine cells (PNECs) contain abundant gastrin- releasing peptide (GRP, mammalian bombesin-like peptide [BLP]). Previo usly, addition of bombesin resulted in increased fetal lung growth and maturation in utero and in organ cultures. A monoclonal antibody (mAb ) to bombesin (2A11) blocked baseline automaturation of lung organ cul tures in serum-free medium. In the present study, we analyze lung deve lopment following daily in utero administration of 2A11 from gestation al days 15-18. Fetal lung treated with 2A11 and then harvested on day 18 demonstrated a dose-dependent decrease in surfactant phospholipid s ynthesis compared to controls treated with MOPC, an unreactive mAb. Ho wever, 2A11-treated fetal lung harvested on day 17 showed paradoxical increases in H-3-choline incorporation into saturated phosphatidylchol ine, H-3-thymidine incorporation into DNA, and relative numbers of dif ferentiated type II pneumocytes. In serum-containing day 17 lung organ cultures, 2A11 stimulated choline and thymidine incorporation. Since epidermal growth factor (EGF) is the only agent besides bombesin known to stimulate both fetal lung growth and maturation, we added EGF to s erum-free cultures and reconstituted the stimulatory effects. A murine EGF receptor mAb (ERA) blocked 2A11-induced lung growth and maturatio n in serum-containing cultures, and this effect was overcome by adding EGF. In vivo, ERA also blocked stimulatory effects of 2A11 in fetal l ung on day 17. These observations suggest that EGF receptor up-regulat ion may maintain lung growth and maturation if BLP levels are diminish ed on day 17. Nonetheless, BLPs appear to be involved in lung maturati on on day 18, supporting a role for PNECs in normal lung development.