Dataset Information

Bombesin inhibits alveolarization and promotes pulmonary fibrosis in newborn mice.

ABSTRACT:

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.

SUBMITTER: Ashour K

PROVIDER: S-EPMC2662976 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlthough bronchopulmonary dysplasia is closely associated with an arrest of alveolar development and pulmonary capillary dysplasia, it is unknown whether these two features are causally related. To investigate the relationship between pulmonary capillaries and alveolar formation, we partially embolized the pulmonary capillary bed.MethodsPartial pulmonary embolization (PPE) was induced in chronically catheterized fetal sheep by injection of microspheres into the left pulmonary artery for 1 day (1d PPE; 115d gestational age; GA) or 5 days (5d PPE; 110-115d GA). Control fetuses received vehicle injections. Lung morphology, secondary septal crests, elastin, collagen, myofibroblast, PECAM1 and HIF1 alpha abundance and localization were determined histologically. VEGF-A, Flk-1, PDGF-A and PDGF-R alpha mRNA levels were measured using real-time PCR.ResultsAt 130d GA (term approximately 147d), in embolized regions of the lung the percentage of lung occupied by tissue was increased from 29 +/- 1% in controls to 35 +/- 1% in 1d PPE and 44 +/- 1% in 5d PPE fetuses (p < 0.001). Secondary septal crest density was reduced from 8 +/- 0% in controls to 5 +/- 0% in 1d PPE and 4 +/- 0% in 5d PPE fetuses (p < 0.05), indicating impaired alveolar formation. The deposition of differentiated myofibroblasts (23 +/- 1% vs 28 +/- 1%; p < 0.001) and elastin fibres (3 +/- 0% vs 4 +/- 0%; p < 0.05) were also impaired in embolized lung regions of PPE fetuses compared to controls. PPE did not alter the deposition of collagen or PECAM1. At 116d GA in 5d PPE fetuses, markers of hypoxia indicated that a small and transient hypoxic event had occurred (hypoxia in 6.7 +/- 1.4% of the tissue within embolized regions of 5d PPE fetuses at 116d compared to 0.8 +/- 0.2% of tissue in control regions). There was no change in the proportion of tissue labelled with HIF1 alpha. There was no change in mRNA levels of the angiogenic factors VEGF and Flk-1, although a small increase in PDGF-R alpha expression at 116d GA, from 1.00 +/- 0.12 in control fetuses to 1.61 +/- 0.18 in 5d PPE fetuses may account for impaired differentiation of alveolar myofibroblasts and alveolar development.ConclusionsPPE impairs alveolarization without adverse systemic effects and is a novel model for investigating the role of pulmonary capillaries and alveolar myofibroblasts in alveolar formation.