Bombesin inhibits alveolarization and promotes pulmonary fibrosis in newborn mice

Am J Respir Crit Care Med. 2006 Jun 15;173(12):1377-85. doi: 10.1164/rccm.200507-1014OC. Epub 2006 Apr 7.


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 wild-type 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / analysis
  • Animals
  • Animals, Newborn
  • Bombesin / administration & dosage
  • Bombesin / adverse effects*
  • Cell Proliferation / drug effects
  • Fibroblasts / drug effects
  • Gastrin-Releasing Peptide / administration & dosage
  • Gastrin-Releasing Peptide / pharmacology
  • Gastrointestinal Agents / administration & dosage
  • Gastrointestinal Agents / pharmacology
  • Injections, Intraperitoneal
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurokinin B / analogs & derivatives
  • Neurokinin B / physiology
  • Neurotransmitter Agents / administration & dosage
  • Neurotransmitter Agents / adverse effects*
  • Proliferating Cell Nuclear Antigen / analysis
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / pathology
  • Pulmonary Fibrosis / chemically induced*
  • Receptors, Bombesin / physiology


  • Actins
  • Gastrointestinal Agents
  • Ligands
  • Neurotransmitter Agents
  • Proliferating Cell Nuclear Antigen
  • Receptors, Bombesin
  • bombesin receptor subtype 3
  • Gastrin-Releasing Peptide
  • Neurokinin B
  • neuromedin B
  • Bombesin