Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary Dysplasia

Abstract

Rationale: The incidence of bronchopulmonary dysplasia (BPD), a 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 pro re nata [PRN], called the 125-day PRN model), similar to ''modern-day BPD.'' Methods: The 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 bombesinlike 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 eightfold 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 branch points per millimeter squared. Bombesin promoted tubulogenesis of cultured pulmonary microvascular endothelial cells, but cocultured fetal lung mesenchymal cells abrogated this effect. Conclusions: Early bombesin-like peptide overproduction in 125-day PRN animals predicted alveolarization defects weeks later. Bombesinlike peptide blockade improved septation, with the greatest effects at P21. This could have implications for preventing BPD in premature infants.Keywords: bombesin; gastrin-releasing peptide; mechanical ventilation; prematurity; antibody treatment Bronchopulmonary dysplasia (BPD) is a chronic lung disease of newborns, often following respiratory distress syndrome. The etiology of BPD remains enigmatic, although it has been associated with multiple factors, including mechanical ventilation, oxygen therapy, infection, inflammatory mediators, and immaturity (1-3). ''Old BPD,'' described by Northway (4), was characterized by airway injury, inflammation, segments of atelectasis alternating with cystic overexpansion, and interstitial fibrosis. Such severe BPD is now less prevalent due to improved medical care. However, BPD is still a major burden in pediatric medicine, paradoxically due to success in improving acute survival. BPD affects approximately 30% of infants weighing less than 1,000 g. ''Modernday BPD,'' occurring in infants less than 30 weeks' gestation, seems to have a different pathophysiology and is characterized by arrested alveolar development and microvascular defects (3,(5)(6)(7)(8).Although many animal models of BPD have been described (9-15), BPD in preterm baboons is most similar to human BPD clinically and path...

RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

“…Consistent with GRPR mRNA in PMN, macrophages, and T cells, GRP blockade suppresses acute and chronic inflammation in both O 3 and OVA models. In baboon models of BPD (6,20), GRP blockade normalizes thymic maturation and T cell responses and reduces CD4 + T cells in the pulmonary interstitium (28). GRP blockade could arrest migration of peribronchiolar CD4 + T cells, which contribute to airways inflammation in mice and asthma in humans (51).…”

“…GRP is present at high levels in human and mouse fetal lung (17,18), and GRP regulates normal development (18,19). However, excessive GRP can promote disease (20). Several observations led to our hypothesis that GRP contributes to asthma.…”

“…Children with primary PNEC hyperplasia, termed neuroendocrine cell hyperplasia of infancy (NEHI), have air trapping and elevated airways reactivity (25). GRP levels double in premature newborns that later develop BPD (6,20,26). GRP blockade abrogates acute and chronic lung injury in baboon models of BPD (6,20).…”

“…GRP levels double in premature newborns that later develop BPD (6,20,26). GRP blockade abrogates acute and chronic lung injury in baboon models of BPD (6,20). GRP as a mediator of lung injury in BPD is relevant to asthma because BPD patients have ≈5-to 10-fold increased risk for developing asthma (7,8).…”

Animal models of bronchopulmonary dysplasia. The preterm baboon models

“…Several different approaches to prevent BPD have been investigated in this model including upregulation of hypoxia inducible factor 1, superoxide dismutase mimetics, anti-bombesin antibodies, inhaled nitric oxide, retinoic acid, patent ductus arteriosus (PDA) closure, and high-frequency ventilation (3,17,18,49,50,60,72,92). The most promising interventional results, however, were seen with early transition to nasal continuous positive airway pressure.…”