“New” Bronchopulmonary Dysplasia

Bhandari, Anita; Bhandari, Vineet

doi:10.1097/cpm.0b013e318218a071

Cited by 36 publications

(44 citation statements)

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“…Exposure of the developing lung to hyperoxia is a critical factor in the occurrence of BPD [1,5], thus highlighting the need for understanding the role of hyperoxia among the environmental factors contributing to “new” BPD [1,6,7]. An improved understanding of the mechanisms of hyperoxia-induced lung injury in the context of the role of host mediators such as MIF would be helpful in formulating potential therapeutic strategies with the goal of ameliorating BPD [7,8].…”

Section: Introductionmentioning

confidence: 99%

Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia

et al. 2013

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BackgroundThe role and mechanism of action of MIF in bronchopulmonary dysplasia (BPD) are not known. We hypothesized that increased MIF signaling would ameliorate the pulmonary phenotype of BPD in the mouse lung.MethodsWe studied newborn wild type (WT), MIF knockout (MIFKO), and lung MIF transgenic (MIFTG) mice in room air and a BPD model, and examined the effects of administering a small molecule MIF agonist and antagonist. Lung morphometry was performed and mRNA and protein expression of vascular mediators were analyzed.ResultsThe pulmonary phenotype of MIFKO and MIFTG mice lungs in room air (RA) and BPD model were comparable to the WT-BPD mice at postnatal (PN) day 14. Vascular endothelial growth factor (VEGF)-A, -R1 and Angiopoietin (Ang)1 mRNA were decreased, and Ang2 increased in the WT-BPD, MIFKO-RA, MIFKO-BPD, MIFTG-RA and MIFTG-BPD mice lungs, compared to appropriate controls. The protein expression of Ang1 in the MIFKO-RA was similar to WT-RA, but decreased in MIFTG-RA, and decreased in all the BPD groups. Ang2 was increased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. Tie2 was increased in WT-BPD compared to WT-RA, but decreased in MIFKO- and MIFTG- RA and BPD groups. VEGFR1 was uniformly decreased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. VEGF-A had a similar expression across all RA and BPD groups. There was partial recovery of the pulmonary phenotype in the WT-BPD model treated with the MIF agonist, and in the MIFTG mice treated with the MIF antagonist.ConclusionsThese data point to the careful regulatory balance exerted by MIF in the developing lung and response to hyperoxia and support the potential therapeutic value of small molecule MIF modulation in BPD.

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Section: Introductionmentioning

confidence: 99%

Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia

et al. 2013

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“…There are limitations to hyperoxia models. Based on the correlation between mouse and human lung development, timing of such experiments may preferably be restricted to the first 4 -5 days of PN life, which limits hyperoxia exposure to the saccular stage and the transition to the alveolar stage and reduces fibrosis, which is not a prominent histological characteristic of new BPD (11). Experimental data suggest that variable concentrations of hyperoxia exposure could mimic the differential severity of BPD (23, 50, 91).…”

Section: Rodent Models Of Pulmonary Diseasementioning

confidence: 99%

“…Less prominent are the widespread fibrosis and smooth muscle hypertrophy that were hallmarks of old BPD. This change is thought to reflect differences in the timing and mechanism of lung insult and injury compared with decades past (11).…”

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Animal models of bronchopulmonary dysplasia. The term mouse models

Berger

Bhandari

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Berger J, Bhandari V. Animal models of bronchopulmonary dysplasia. I. The term mouse models. Am J Physiol Lung Cell Mol Physiol 307: L936 -L947, 2014. First published October 10, 2014 doi:10.1152/ajplung.00159.2014.-The etiology of bronchopulmonary dysplasia (BPD) is multifactorial, with genetics, ante-and postnatal sepsis, invasive mechanical ventilation, and exposure to hyperoxia being well described as contributing factors. Much of what is known about the pathogenesis of BPD is derived from animal models being exposed to the environmental factors noted above. This review will briefly cover the various mouse models of BPD, focusing mainly on the hyperoxia-induced lung injury models. We will also include hypoxia, hypoxia/hyperoxia, inflammation-induced, and transgenic models in room air. Attention to the stage of lung development at the timing of the initiation of the environmental insult and the duration of lung injury is critical to attempt to mimic the human disease pulmonary phenotype, both in the short term and in outcomes extending into childhood, adolescence, and adulthood. The various indexes of alveolar and vascular development as well as pulmonary function including pulmonary hypertension will be highlighted. The advantages (and limitations) of using such approaches will be discussed in the context of understanding the pathogenesis of and targeting therapeutic interventions to ameliorate human BPD.

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“…Premature infants diagnosed with BPD have diminished pulmonary function and reduced lung capacity as they grow older and up to adulthood (3). This disease represents a common yet complicated clinical issue associated with significant long-term morbidity and mortality (2,3). Pulmonary-specific oxygen toxicity is usually referred to as hyperoxia-induced acute lung injury (HALI).…”

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“…BPD occurs in developing lungs resulting in impaired alveolarization and dysregulated vascularization-the pathologic hallmarks (2). Premature infants diagnosed with BPD have diminished pulmonary function and reduced lung capacity as they grow older and up to adulthood (3).…”

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confidence: 99%

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

Sureshbabu

Syed

Das

et al. 2016

Am J Respir Cell Mol Biol

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Administration of supplemental oxygen remains a critical clinical intervention for survival of preterm infants with respiratory failure. However, prolonged exposure to hyperoxia can augment pulmonary damage, resulting in developmental lung diseases embodied as hyperoxia-induced acute lung injury and bronchopulmonary dysplasia (BPD). We sought to investigate the role of autophagy in hyperoxia-induced apoptotic cell death in developing lungs. We identified increased autophagy signaling in hyperoxia-exposed mouse lung epithelial-12 cells, freshly isolated fetal type II alveolar epithelial cells, lungs of newborn wild-type mice, and human newborns with respiratory distress syndrome and evolving and established BPD. We found that hyperoxia exposure induces autophagy in a Trp53-dependent manner in mouse lung epithelial-12 cells and in neonatal mouse lungs. Using pharmacological inhibitors and gene silencing techniques, we found that the activation of autophagy, upon hyperoxia exposure, demonstrated a protective role with an antiapoptotic response. Specifically, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) in hyperoxia settings, as evidenced by wild-type mice treated with torin2 or mice administered (Rptor) silencing RNA via intranasal delivery or Rptor 1/2 , limited lung injury by increased autophagy, decreased apoptosis, improved lung architecture, and increased survival. Furthermore, we identified increased protein expression of phospho-beclin1, light chain-3-II and lysosomalassociated membrane protein 1, suggesting altered autophagic flux in the lungs of human neonates with established BPD. Collectively, our study unveils a novel demonstration of enhancing autophagy and antiapoptotic effects, specifically through the inhibition of RPTOR as a potentially useful therapeutic target for the treatment of hyperoxia-induced acute lung injury and BPD in developing lungs.Keywords: cell death; oxygen; newborn; pulmonary; bronchopulmonary dysplasia Premature infants provided with supplemental oxygen are at higher risk for developing a chronic respiratory disease, bronchopulmonary dysplasia (BPD) (1). BPD occurs in developing lungs resulting in impaired alveolarization and dysregulated vascularization-the pathologic hallmarks (2). Premature infants diagnosed with BPD have diminished pulmonary function and reduced lung capacity as they grow older and up to adulthood (3). This disease represents a common yet complicated clinical issue associated with significant long-term morbidity and mortality (2, 3). Pulmonary-specific oxygen toxicity is This work was supported in part by National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) grants HL63039 (G.P.) and HL116632 (A.R.), by the Sigrid Jusélius Foundation (S.A.), and by NHLBI/NIH grant HL85103 (V.B.).Author Contributions: Concept and design-A.S. and V.B.; acquisition of data-A.S., M.S., P.D., C.J., G.P., A.R., S.A., R.J.H., and V.B.; data analysis and interpretation-A.S., M.S., P.D., C.J., G.P., A.R., S...

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“New” Bronchopulmonary Dysplasia

Cited by 36 publications

References 60 publications

Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia

Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia

Animal models of bronchopulmonary dysplasia. The term mouse models

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

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