Potential Role for Antiangiogenic Proteins in the Evolution of Bronchopulmonary Dysplasia

Quintos-Alagheband, Maria Lyn; White, Carl W.; Schwarz, Margaret A.

doi:10.1089/152308604771978444

Cited by 25 publications

(20 citation statements)

References 20 publications

(21 reference statements)

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“…Pathological consequences of EMAPII excess include the inhibition of neovascularization and airway epithelial morphogenesis in the developing lung (44)(45)(46). Our results add lung alveolar endothelial apoptosis and inflammation leading to emphysema-like disease as novel pathogenic roles for EMAPII.…”

Section: Figurementioning

confidence: 63%

Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice

et al. 2011

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Pulmonary emphysema is a disease characterized by alveolar cellular loss and inflammation. Recently, excessive apoptosis of structural alveolar cells has emerged as a major mechanism in the development of emphysema. Here, we investigated the proapoptotic and monocyte chemoattractant cytokine endothelial monocyte-activating protein 2 (EMAPII). Lung-specific overexpression of EMAPII in mice caused simplification of alveolar structures, apoptosis, and macrophage accumulation, compared with that in control transgenic mice. Additionally, in a mouse model of cigarette smoke-induced (CS-induced) emphysema, EMAPII levels were significantly increased in murine lungs. This upregulation was necessary for emphysema development, as neutralizing antibodies to EMAPII resulted in reduced alveolar cell apoptosis, inflammation, and emphysema-associated structural changes in alveoli and small airways and improved lung function. The mechanism of EMAPII upregulation involved an apoptosis-dependent feed-forward loop, since caspase-3 instillation in the lung markedly increased EMAPII expression, while caspase inhibition decreased its production, even in transgenic EMAPII mice. These findings may have clinical significance, as both current smokers and exsmoker chronic obstructive pulmonary disease (COPD) patients had increased levels of secreted EMAPII in the bronchoalveolar lavage fluid compared with that of nonsmokers. In conclusion, we suggest that EMAPII perpetuates the mechanism of CS-induced lung emphysema in mice and, given its secretory nature, is a suitable target for neutralization antibody therapy.

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Section: Figurementioning

confidence: 63%

Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice

et al. 2011

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“…Impaired angiogenesis has been observed in many studies of infants and baboons with BPD (3,7,19,47). In contrast, De Paepe and colleagues have described an increase in total pulmonary microvascular endothelial cell volume in long-term ventilated infants (8).…”

Section: Discussionmentioning

confidence: 99%

Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary Dysplasia

Subramaniam

Bausch

Twomey

et al. 2007

Am J Respir Crit Care Med

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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...

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“…Previously, we identified an association between elevated EMAP II levels and BPD in premature baboons and human infants (31). As a result, we hypothesized that EMAP II drives macrophage recruitment in BPD, which intensifies the inflammatory state.…”

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confidence: 87%

Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity

Lee

Lal

Persad

et al. 2016

Am J Respir Cell Mol Biol

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Myeloid cells are key factors in the progression of bronchopulmonary dysplasia (BPD) pathogenesis. Endothelial monocyte-activating polypeptide II (EMAP II) mediates myeloid cell trafficking. The origin and physiological mechanism by which EMAP II affects pathogenesis in BPD is unknown. The objective was to determine the functional consequences of elevated EMAP II levels in the pathogenesis of murine BPD and to investigate EMAP II neutralization as a therapeutic strategy. Three neonatal mouse models were used: (1) BPD (hyperoxia), (2) EMAP II delivery, and (3) BPD with neutralizing EMAP II antibody treatments. Chemokinic function of EMAP II and its neutralization were assessed by migration in vitro and in vivo. We determined the location of EMAP II by immunohistochemistry, pulmonary proinflammatory and chemotactic gene expression by quantitative polymerase chain reaction and immunoblotting, lung outcome by pulmonary function testing and histological analysis, and right ventricular hypertrophy by Fulton's Index. In BPD, EMAP II initially is a bronchial clubcell-specific protein-derived factor that later is expressed in galectin-3 1 macrophages as BPD progresses. Continuous elevated expression corroborates with baboon and human BPD. Prolonged elevation of EMAP II levels recruits galectin-3 1 macrophages, which is followed by an inflammatory state that resembles a severe BPD phenotype characterized by decreased pulmonary compliance, arrested alveolar development, and signs of pulmonary hypertension. In vivo pharmacological EMAP II inhibition suppressed proinflammatory genes Tnfa, Il6, and Il1b and chemotactic genes Ccl2 and Ccl9 and reversed the severe BPD phenotype. EMAP II is sufficient to induce macrophage recruitment, worsens BPD progression, and represents a targetable mechanism of BPD development.

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Potential Role for Antiangiogenic Proteins in the Evolution of Bronchopulmonary Dysplasia

Cited by 25 publications

References 20 publications

Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice

Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice

Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary Dysplasia

Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity

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