Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung

1 Department of Pathology, Children's and Brigham and Women's Hospitals and Harvard Medical School, and 2 Department of Medicine, Children's Hospital, Boston, Massachusetts 02115; 3 Department of Pediatrics, Harbor-UCLA Research and Educational Institute, Torrance, California 90502; 4 Department of Degenerative Neurological Diseases, National Institute of Neuroscience, Tokyo 187-8502; and 5 Japan Society for the Promotion of Science, Tokyo 102-8471, Japan Submitted 18 December 2002 ; accepted in final form 31 July 2003 Bombesin-peptide (BLP) immunoreactivity occurs at high levels in fetal lung. Previous studies showed that bombesin promotes fetal lung development. To test the hypothesis that such effects are mediated by known mammalian bombesin receptors [gastrin-releasing peptide (GRP)/bombesin-preferring receptor (GRPR), neuromedin B (NMB) receptor (NMBR), and the orphan bombesin receptor subtype-3 (BRS-3)], we analyzed the ontogeny of GRPR, NMBR, and BRS-3 gene expression in mouse lung. We examined the regulation of these three genes by dexamethasone and bombesin, which modulate lung development. Using incorporation of [ 3 H]thymidine and [ 3 H]choline, we then assessed whether GRP, NMB, and Leu 8 -phyllolitorin modulate lung growth and maturation in fetal lung explants. GRPR gene expression was detected predominantly in utero, whereas NMBR and BRS-3 genes were expressed from embryonic days 13–16 and on multiple postnatal days. All three mRNAs are present in airway epithelium and mesenchymal cells but occur in different relative patterns. These genes were regulated differently. Dexamethasone and bombesin increased GRPR mRNA, bombesin downregulated NMBR, and neither agent affected BRS-3. GRP increased incorporation of [ 3 H]thymidine and [ 3 H]choline in explants, whereas NMB induced cell proliferation and Leu 8 -phyllolitorin yielded variable results. Cumulative data suggest the involvement of multiple BLP receptors, including novel molecules, and argue against simple functional redundancy within this gene family during lung development. gastrin-releasing peptide; neuromedin B; bombesin receptor subtype 3; dexamethasone; cell proliferation; type II cell differentiation Address for reprint requests and other correspondence: M. E. Sunday, Brigham and Women's Hospital, Dept. of Pathology, 75 Francis St., Boston, MA 02115 (E-mail: sunday{at}tch.harvard.edu ).