Rationale: Bombesin-like peptides promote fetal lung development. Normally, levels of mammalian bombesin (gastrin-releasing peptide [GRP]) drop postnatally, but these levels are elevated in newborns that develop bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by arrested alveolarization. In premature baboons with BPD, antibombesin antibodies reduce lung injury and promote alveolarization. Objectives: The present study tests whether exogenous bombesin or GRP given perinatally alters alveolar development in newborn mice. Methods: Mice were given peptides intraperitoneally twice daily on Postnatal Days 1-3. On Day 14 lungs were inflation-fixed for histopathologic analyses of alveolarization. Measurements and Main Results: Bombesin had multiple effects on Day 14 lung, when alveolarization was about half complete. First, bombesin induced alveolar myofibroblast proliferation and increased alveolar wall thickness compared with saline-treated control animals. Second, bombesin diminished alveolarization in C57BL/6 (but not Swiss-Webster) mice. We used receptor-null mice to explore which receptors might mediate these effects. Compared with wild-type littermates, bombesin-treated GRP receptor (GRPR)-null mice had increased interstitial fibrosis but reduced defects in alveolarization. Neuromedin B (NMB) receptor-null and bombesin receptor subtype 3-null mice had the same responses as their wildtype littermates. GRP had the same effects as bombesin, whereas neither NMB nor a synthetic bombesin receptor type 3 ligand had any effect. All effects of GRP were abrogated in GRPR-null mice. Conclusions: Bombesin/GRP can induce features of BPD, including interstitial fibrosis and diminished alveolarization. GRPR appears to mediate all effects of GRP, but only part of the bombesin effect on alveolarization, suggesting that novel receptors may mediate some effects of bombesin in newborn lung.Keywords: bronchopulmonary dysplasia; gastrin-releasing peptide; interstitial fibrosis; knock-out mice Bombesin is a 14-amino acid peptide originally identified in 1971 by Erspamer in skin of the frog Bombina bombina (1-3). Using antibodies to amphibian bombesin, a 27-amino acid mammalian homolog was identified by McDonald and termed gastrinreleasing peptide (GRP) (4). GRP and bombesin share a highly conserved seven-amino acid C-terminus, which is required for immunogenicity and high-affinity binding to physiologic receptors. Thus, bombesin and GRP are referred to collectively as "bombesin-like peptides" (BLPs), because both peptides bind to and elicit the same physiologic effects at mammalian bombesin/ GRP-preferring receptors. BLP immunoreactivity is widely distributed in the central nervous system, the lung, and the gut, but the highest levels occur in mid-gestation human fetal lung (2, 5).During lung development, the first epithelial cells to differentiate are the pulmonary neuroendocrine cells (6, 7), which contain high levels of BLP immunoreactivity. BLP can promote growth and maturation of developing fetal lung in hum...