Published ahead of print on April 7, 2006, doi:10.1164/rccm.200507-1014OC Am. J. Respir. Crit. Care Med., Volume 173, Number 12, June 2006, 1377-1385 A more recent version of this article appeared on June 15, 2006
Submitted on July 1, 2005 Bombesin Inhibits Alveolarization and Promotes Pulmonary Fibrosis in Newborn MiceKhalid Ashour1,1 Department of Medicine, Division of Neonatology, Children's Hospital, Boston, MA, USA, 2 Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Pathology, Duke University Medical Center, Durham, NC, USA, 3 Department of Pathology, Duke University Medical Center, Durham, NC, USA, 4 Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA, 5 Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan, 6 Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Pathology, Duke University Medical Center, Durham, NC, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA * To whom correspondence should be addressed. E-mail: mary.sunday{at}duke.edu.
Rationale: Bombesin-like peptide (BLP) promotes fetal lung development. Normally levels of mammalian bombesin (gastrin-releasing peptide, GRP) drop postnatally, but these are elevated in newborns that develop bronchopulmonary dysplasia, a chronic lung disease characterized by arrested alveolarization. In premature baboons with bronchopulmonary dysplasia, anti-bombesin 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 histopathological analyses of alveolarization. Measurements and Main Results: Bombesin has multiple effects on day 14 lung, when alveolarization is about half-complete. First, bombesin induces alveolar myofibroblast proliferation and increased alveolar wall thickness compared to saline-treated controls. Second, bombesin diminishes alveolarization in C57BL/6 (but not Swiss-Webster) mice. We utilized receptor-null mice to explore which receptors might mediate these effects. Compared to wild-type littermates, bombesin-treated GRPR-null mice have increased interstitial fibrosis but reduced defects in alveolarization. NMBR-null and BRS-3-null mice have the same responses as their wild-type littermates. GRP has the same effects as bombesin, whereas neither NMB nor a synthetic BRS3 ligand has any effect. All effects of GRP are abrogated in GRPR-null mice. Conclusions: Bombesin/GRP can induce features of bronchopulmonary dysplasia, 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. Key words: bronchopulmonary dysplasia, interstitial fibrosis, knockout mice, gastrin-releasing peptide
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