Published ahead of print on June 21, 2007, doi:10.1164/rccm.200611-1734OC Am. J. Respir. Crit. Care Med., Volume 176, Number 9, November 2007, 902-912 A more recent version of this article appeared on November 1, 2007
Submitted on November 29, 2006 Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary DysplasiaMeera Subramaniam1,1 Department of Medicine and Pathology, Pulmonary Division, Brigham and Women's Hospital, Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Division of Pulmonary Medicine, Children's Hopsital and Harvard Medical School, Boston, MA, USA, 2 Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA, 3 Department of Pediatrics, Division of Pulmonary Medicine, Children's Hopsital and Harvard Medical School, Boston, MA, USA, 4 Southwest Foundation for Biomedical Research, San Antonio, TX, USA, 5 National Jewish Medical and Research Center, Denver, CO, USA, 6 Washington University Medical Center, St. Louis, MO, USA, 7 Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, 8 Department of Medicine and Pathology, Pulmonary Division, Brigham and Women's Hospital, Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA * To whom correspondence should be addressed. E-mail: mary.sunday{at}duke.edu.
Rationale: The incidence of bronchopulmonary dysplasia (BPD), chronic lung disease of newborns, is paradoxically rising despite medical advances. We demonstrated elevated bombesin-like peptide levels in infants that later developed BPD. In the 140-day hyperoxic baboon model of BPD, anti-bombesin antibody 2A11 abrogated lung injury. Objectives: To test the hypothesis that bombesin-like peptides mediate BPD in extremely premature baboons (born at gestational day 125 and given oxygen as needed, called the 125-day PRN model), similar to modern-day BPD. Methods: 125-day animals were treated with 2A11 on postnatal day 1 (P1), P3, and P6. On P14 and P21, lungs were inflation-fixed for histopathologic analyses of alveolarization. Regulation of angiogenesis by bombesin was evaluated using cultured pulmonary microvascular endothelial cells. Measurements and Main Results: In 125-day PRN animals, urine bombesin-like peptide levels at P2-3 are directly correlated with impaired lung function at P14. Gastrin-releasing peptide (the major pulmonary bombesin-like peptide) mRNA was elevated 8-fold at P1 and remained high thereafter. At P14, 2A11 reduced alveolar wall thickness and increased the percentage of secondary septa containing endothelial cells. At P21, 2A11-treated 125-day PRN animals had improved alveolarization according to mean linear intercepts and number of branchpoints/mm2. Bombesin promoted tubulogenesis of cultured pulmonary microvascular endothelial cells, but co-cultured fetal lung mesenchymal cells abrogated this effect. Conclusions: Early bombesin-like peptide overproduction in 125-day PRN animals predicted alveolarization defects weeks later. Bombesin-like peptide blockade improved septation, with greatest effects at P21. This could have implications for preventing BPD in premature infants. Key words: bombesin, gastrin-releasing peptide, mechanical ventilation, prematurity, antibody treatment
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